Substituted Oxazole- and Thiazole-Based Carboxamide and Urea Derivatives as Vanilloid Receptor Ligands II

ABSTRACT

The invention relates to oxazole and thiazole-based carboxamide and urea derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/EP2015/002362, filed Nov. 24,2015, which claims the benefit of EP Application No. 14003949.6, filedNov. 24, 2014. Both of these applications are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

The invention relates to substituted oxazole and thiazole-basedcarboxamide and urea derivatives as vanilloid receptor ligands, topharmaceutical compositions containing these compounds and also to thesecompounds for use in the treatment and/or prophylaxis of pain andfurther diseases and/or disorders.

BACKGROUND OF THE INVENTION

The treatment of pain, in particular of neuropathic pain, is veryimportant in medicine. There is a worldwide demand for effective paintherapies. The urgent need for action for a patient-focused andtarget-oriented treatment of chronic and non-chronic states of pain,this being understood to mean the successful and satisfactory treatmentof pain for the patient, is also documented in the large number ofscientific studies which have recently appeared in the field of appliedanalgesics or basic research on nociception.

The subtype 1 vanilloid receptor (VR1/TRPV1), which is often alsoreferred to as the capsaicin receptor, is a suitable starting point forthe treatment of pain, in particular of pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain and visceralpain. This receptor is stimulated inter alia by vanilloids such ascapsaicin, heat and protons and plays a central role in the formation ofpain. In addition, it is important for a large number of furtherphysiological and patho-physiological processes and is a suitable targetfor the therapy of a large number of further disorders such as, forexample, migraine, depression, neurodegenerative diseases, cognitivedisorders, states of anxiety, epilepsy, coughs, diarrhoea, pruritus,inflammations, disorders of the cardiovascular system, eating disorders,medication dependency, misuse of medication and urinary incontinence.

There is a demand for further compounds having comparable or betterproperties, not only with regard to affinity to vanilloid receptors 1(VR1/TRPV1 receptors) per se (potency, efficacy).

Thus, it may be advantageous to improve the metabolic stability, thesolubility in aqueous media or the permeability of the compounds. Thesefactors can have a beneficial effect on oral bioavailability or canalter the PK/PD (pharmacokinetic/pharmacodynamic) profile; this can leadto a more beneficial period of effectiveness, for example. A weak ornon-existent interaction with transporter molecules, which are involvedin the ingestion and the excretion of pharmaceutical compositions, isalso to be regarded as an indication of improved bioavailability and atmost low interactions of pharmaceutical compositions. Furthermore, theinteractions with the enzymes involved in the decomposition and theexcretion of pharmaceutical compositions should also be as low aspossible, as such test results also suggest that at most lowinteractions or no interactions at all, of pharmaceutical compositionsare to be expected.

It was therefore an object of the invention to provide novel compounds,preferably having advantages over the prior-art compounds. The compoundsshould be suitable in particular as pharmacological active ingredientsin pharmaceutical compositions, preferably in pharmaceuticalcompositions for the treatment and/or prophylaxis of disorders ordiseases which are at least partially mediated by vanilloid receptors 1(VR1/TRPV1 receptors).

This object is achieved by the subject matter described herein.

It has surprisingly been found that the substituted compounds of generalformula (I), as given below, display outstanding affinity to the subtype1 vanilloid receptor (VR1/TRPV1 receptor) and are therefore particularlysuitable for the prophylaxis and/or treatment of disorders or diseaseswhich are at least partially mediated by vanilloid receptors 1(VR1/TRPV1).

Particularly suitable are substituted compounds of general formula (I),as given below, that in addition to their activity with regard to theVR1-receptor show one or more additional advantageous properties, forexample, suitable potency, suitable efficacy, no increase in bodytemperature and/or heat pain threshold; appropriate solubility inbiologically relevant media such as aqueous media, in particular inaqueous media at a physiologically acceptable pH value, such as inbuffer systems, for instance in phosphate buffer systems; suitablemetabolic stability and diversity (e.g. sufficient stability towards theoxidative capabilities of hepatic enzymes such as cytochrome P450 (CYP)enzymes and sufficient diversity with regard to the metabolicelimination via these enzymes); and the like.

In a first aspect of the present invention, the present inventionrelates to a substituted compound of general formula (I),

wherein

-   X represents O or S;-   Y represents O, S or N—CN;-   Z represents N(R^(3b)) or C(R^(4a)R^(4b));-   R¹ represents aryl or heteroaryl,    -   wherein said aryl or heteroaryl may be unsubstituted or mono- or        independently polysubstituted by one or more substituents,        selected from the group consisting of H, F, Cl, Br, CN, OH,        C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,        cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,        halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy,        C₁₋₄-alkylS(O), hydroxy-C₁₋₄-alkylS(O), halo-C₁₋₄-alkylS(O),        cyano-C₁₋₄-alkylS(O), C₁₋₄-alkoxy-C₁₋₄-alkylS(O),        C₁₋₄-alkylS(O)₂, hydroxy-C₁₋₄-alkylS(O)₂, halo-C₁₋₄-alkylS(O)₂,        cyano-C₁₋₄-alkylS(O)₂, C₁₋₄-alkoxy-C₁₋₄-alkylS(O)₂, H₂N,        (C₁₋₄-alkyl)(H)N, (hydroxy-C₁₋₄-alkyl)(H)N,        (halo-C₁₋₄-alkyl)(H)N, (cyano-C₁₋₄-alkyl)(H)N,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N, (C₃₋₆-cycloalkyl)(H)N,        (C₃₋₇-heterocycloalkyl)(H)N, (C₁₋₄-alkyl)₂N,        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N,        (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N, (hydroxy-C₁₋₄-alkyl)₂N,        (C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)N and        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N,-   R² represents C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,    cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, C₃₋₆-cycloalkyl or    (C₃₋₆-cycloalkyl)-C₁₋₄-alkyl;-   R^(3a) and R^(3b) each independently represent H, C₁₋₄-alkyl,    hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl or    C₁₋₄-alkoxy-C₁₋₄-alkyl;-   R^(4a) and R^(4b) each independently represent H, F, Cl, CN,    C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl or    C₁₋₄-alkoxy-C₁₋₄-alkyl;-   or-   R^(4a) and R^(4b) together with the carbon atom connecting them form    a C₃₋₆-cycloalkyl or a C₃₋₇-heterocycloalkyl;-   Ar represents aryl or heteroaryl,    -   wherein said aryl or heteroaryl may be condensed with an        aromatic or aliphatic ring to form a bicycle,    -   and wherein said aryl or heteroaryl and said condensed aromatic        or aliphatic ring each independently may be unsubstituted or        mono- or independently polysubstituted by one or more        substituents, selected from the group consisting of F, Cl, Br,        CN, OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,        cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,        halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy,        hydroxy-C₁₋₄-alkoxy-C₁₋₄-alkyl, C₁₋₄-alkylS(O),        hydroxy-C₁₋₄-alkylS(O), halo-C₁₋₄-alkylS(O),        cyano-C₁₋₄-alkylS(O), C₁₋₄-alkoxy-C₁₋₄-alkylS(O),        C₁₋₄-alkylS(O)₂, hydroxy-C₁₋₄-alkylS(O)₂, halo-C₁₋₄-alkylS(O)₂,        cyano-C₁₋₄-alkylS(O)₂, C₁₋₄-alkoxy-C₁₋₄-alkylS(O)₂,        C₁₋₄-alkylS(O)C₁₋₄-alkyl, hydroxy-C₁₋₄-alkylS(O)C₁₋₄-alkyl,        C₁₋₄-alkylS(O)₂C₁₋₄-alkyl, hydroxy-C₁₋₄-alkylS(O)₂C₁₋₄-alkyl,        H₂N, (C₁₋₄-alkyl)(H)N, (hydroxy-C₁₋₄-alkyl)(H)N,        (halo-C₁₋₄-alkyl)(H)N, (cyano-C₁₋₄-alkyl)(H)N,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N, (C₃₋₆-cycloalkyl)(H)N,        (C₃₋₇-heterocycloalkyl)(H)N, (C₁₋₄-alkyl)₂N,        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N,        (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N, (hydroxy-C₁₋₄-alkyl)₂N,        (C₃₋₆-cyclo-alkyl)(hydroxy-C₁₋₄-alkyl)N,        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N, (H)₂NC₁₋₄-alkyl,        [(C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(hydroxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(halo-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(cyano-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(C₃₋₆-cycloalkyl)(H)N](C₁₋₄-alkyl),        [(C₃₋₇-heterocycloalkyl)(H)N](C₁₋₄-alkyl),        [(C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),        [(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(hydroxy-C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),        [(C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl),        H₂NC(O), (C₁₋₄-alkyl)(H)NC(O), (hydroxy-C₁₋₄-alkyl)(H)NC(O),        (halo-C₁₋₄-alkyl)(H)NC(O), (cyano-C₁₋₄-alkyl)(H)NC(O),        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)NC(O), (C₃₋₆-cyclo-alkyl)(H)NC(O),        (C₃₋₇-heterocycloalkyl)(H)NC(O), (C₁₋₄-alkyl)₂NC(O),        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NC(O),        (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)NC(O),        (hydroxy-C₁₋₄-alkyl)₂NC(O),        (C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(O),        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(O), H₂NS(O)₂,        (C₁₋₄-alkyl)(H)NS(O)₂, (hydroxy-C₁₋₄-alkyl)(H)NS(O)₂,        (halo-C₁₋₄-alkyl)(H)NS(O)₂, (cyano-C₁₋₄-alkyl)(H)NS(O)₂,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)—NS(O)₂, (C₃₋₆-cycloalkyl)(H)NS(O)₂,        (C₃₋₇-heterocycloalkyl)(H)NS(O)₂, (C₁₋₄-alkyl)₂NS(O)₂,        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NS(O)₂,        (C₃₋₇-hetero-cycloalkyl)(C₁₋₄-alkyl)NS(O)₂,        (hydroxy-C₁₋₄-alkyl)₂NS(O)₂,        (C₃₋₆-cycloalkyl)-(hydroxy-C₁₋₄-alkyl)NS(O)₂,        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)-NS(O)₂,        H₂NS(O)₂N(H)C₁₋₄-alkyl, (C₁₋₄-alkyl)(H)NS(O)₂N(H)C₁₋₄-alkyl,        (hydroxy-C₁₋₄-alkyl)(H)NS(O)₂N(H)C₁₋₄-alkyl,        (C₁₋₄-alkyl)₂NS(O)₂N(H)C₁₋₄-alkyl,        (C₁₋₄-alkyl)S(O)₂N(H)C₁₋₄-alkyl,        (hydroxy-C₁₋₄-alkyl)S(O)₂N(H)C₁₋₄-alkyl, C₃₋₆-cycloalkyl,        (C₃₋₆-cycloalkyl)-C₁₋₄-alkyl, (C₃₋₆-cycloalkyl)-C₁₋₄-alkoxy,        C₃₋₇-heterocycloalkyl, (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkyl,        (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkoxy,        -   wherein said C₃₋₆-cycloalkyl or C₃₋₇-heterocycloalkyl may be            unsubstituted or mono- or independently polysubstituted by            one or more substituents, selected from H, F, Cl, Br, CN,            OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,            cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,            hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and            C₁₋₄-alkoxy-C₁₋₄-alkoxy;    -   aryl, heteroaryl, (aryl)C₁₋₄-alkyl or (heteroaryl)C₁₋₄-alkyl,        -   wherein said aryl or heteroaryl may be unsubstituted or            mono- or independently polysubstituted by one or more            substituents, selected from the group consisting of H, F,            Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,            halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,            hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and            C₁₋₄-alkoxy-C₁₋₄-alkoxy;            optionally in the form of a single stereoisomer or a mixture            of stereoisomers, in the form of the free compound and/or a            physiologically acceptable salt or a solvate thereof.

DETAILED DESCRIPTION

The term “single stereoisomer” preferably means in the sense of thepresent invention an individual enantiomer or diastereomer. The term“mixture of stereoisomers” means in the sense of this invention theracemate and mixtures of enantiomers and/or diastereomers in any mixingratio.

The term “physiologically acceptable salt” preferably comprises in thesense of this invention a salt of at least one compound according to thepresent invention and at least one physiologically acceptable acid orbase. A physiologically acceptable salt of at least one compoundaccording to the present invention and at least one physiologicallyacceptable acid preferably refers in the sense of this invention to asalt of at least one compound according to the present invention with atleast one inorganic or organic acid which is physiologicallyacceptable—in particular when used in human beings and/or other mammals.A physiologically acceptable salt of at least one compound according tothe present invention and at least one physiologically acceptable basepreferably refers in the sense of this invention to a salt of at leastone compound according to the present invention as an anion with atleast one preferably inorganic cation, which is physiologicallyacceptable—in particular when used in human beings and/or other mammals.

The term “physiologically acceptable solvate” preferably comprises inthe sense of this invention an adduct of one compound according to thepresent invention and/or a physiologically acceptable salt of at leastone compound according to the present invention with distinct molecularequivalents of one solvent or more solvents.

Unless otherwise specified, the term “C₁-C₄-alkyl” (“(C₁-C₄)-alkyl”) isunderstood to mean branched and unbranched alkyl groups consisting of 1to 4 carbon atoms which is optionally mono- or polysubstituted. Examplesof C₁-C₄-alkyl are methyl, ethyl, n-propyl, 1-methylethyl (2-propyl;isopropyl), n-butyl, 1-methylpropyl (2-butyl), 2-methylpropyl,1,1-dimethylethyl (2-(2-methyl)propyl; tert-butyl). C₁-C₃-alkyl areparticularly preferred, in particular methyl, ethyl n-propyl oriso-propyl. Unless otherwise stated, the definitions of propyl and butylencompass all possible isomeric forms of the individual radicals.

Unless otherwise specified, the term “C₁-C₄-alkoxy” is understood tomean branched and unbranched alkyl groups consisting of 1 to 4 carbonatoms which are linked to the subordinate structure residue via anoxygene atom and which is optionally mono- or polysubstituted. Examplesof C₁-C₄-alkoxy are OCH₃, OCH₂CH₃, O(CH₂)₂CH₃, O(CH₂)₃CH₃, OCH(CH₃)₂,OCH₂CH(CH₃)₂, OCH(CH₃)(CH₂CH₃), OC(CH₃)₃. C₁-C₃-alkoxy are particularlypreferred, in particular OCH₃, OCH₂CH₃ or OCH(CH₃)₂.

Unless otherwise specified, a “halo-C₁₋₄-alkyl” is understood to be aC₁₋₄-alkyl in which at least one hydrogen is exchanged for a halogenatom, preferably F, Cl or Br, particularly preferably F. Thehalo-C₁₋₄-alkyl can be branched or unbranched and optionally mono- orpolysubstituted. Preferred halo-C₁₋₄-alkyl are CHF₂, CH₂F, CF₃, CH₂CH₂F,CH₂CHF₂, CH₂CF₃. Halo-C₁-C₃-alkyl are more preferred, in particularCHF₂, CH₂F, CF₃, CH₂CH₂F, CH₂CHF₂ and CH₂CF₃. Unless otherwisespecified, a “halo-C₁₋₄-alkoxy” is understood to be a C₁₋₄-alkoxy inwhich at least one hydrogen is exchanged for a halogen atom, preferablyF, Cl or Br, particularly preferably F. The halo-C₁₋₄-alkoxy can bebranched or unbranched and optionally mono- or polysubstituted.Preferred halo-C₁₋₄-alkoxy are OCHF₂, OCH₂F, OCF₃, OCH₂CFH₂, OCH₂CF₂H,OCH₂CF₃. Halo-C₁₋₃-alkoxy are preferred, in particular OCHF₂, OCH₂F,OCF₃, OCH₂CFH₂, OCH₂CF₂H, OCH₂CF₃.

Unless otherwise specified, a “hydroxy-C₁₋₄-alkyl” radical is to be aC₁₋₄-alkyl in which at least one hydrogen is exchanged for a hydroxylgroup. The hydroxy-C₁₋₄-alkyl can be branched or unbranched andoptionally mono- or polysubstituted. hydroxy-C₁₋₃-alkyl are preferred,in particular CH₂OH, CH₂CH₂OH and CH₂CH₂CH₂OH. Unless otherwisespecified, a “cyano-C₁₋₄-alkyl” is understood to be a C₁₋₄-alkyl inwhich at least one hydrogen is exchanged for a cyano group. Thecyano-C₁₋₄-alkyl can be branched or unbranched and optionally mono- orpolysubstituted. Cyano-C₁₋₃-alkyl are preferred, in particular CH₂CN,CH₂CH₂CN and CH₂CH₂CH₂CN. Unless otherwise specified, a“C₁₋₄-alkoxy-C₁₋₄-alkyl” is understood to be a C₁₋₄-alkyl in which atleast one hydrogen is exchanged for C₁₋₄-alkoxy. TheC₁₋₄-alkoxy-C₁₋₄-alkyl can be branched or unbranched and optionallymono- or polysubstituted. C₁₋₄-alkoxy-C₁₋₃-alkyl are preferred, inparticular CH₂OCH₃, CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₃, CH₂OCH₂CH₃ andCH₂OCH(CH₃)₂.

Unless otherwise specified, a “hydroxy-C₁₋₄-alkoxy”, a“cyano-C₁₋₄-alkoxy” and a “C₁₋₄-alkoxy-C₁₋₄-alkoxy” each is understoodto be a C₁₋₄-alkoxy in which at least one hydrogen is exchanged for ahydroxyl, a cyano or a C₁₋₄-alkoxy. The hydroxy-C₁₋₄-alkoxy,cyano-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy can be branched orunbranched and optionally mono- or polysubstituted. Preferredhydroxy-C₁₋₄-alkoxy are OCH₂CH₂OH and OCH₂CH₂CH₂OH. Preferredcyano-C₁₋₄-alkoxy are OCH₂CN, OCH₂CH₂CN and OCH₂CH₂CH₂CN. PreferredC₁₋₄-alkoxy-C₁₋₄-alkoxy are OCH₂CH₂OCH₃, OCH₂CH₂CH₂OCH₃, OCH(CH₃)OCH₃,OCH₂CH₂OCH₂CH₃ and OCH₂CH₂OCH(CH₃)₂.

The term “C₃₋₆-cycloalkyl” means for the purposes of this inventioncyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms,wherein the hydrocarbons in each case can be unsubstituted or mono- orpolysubstituted. The C₃₋₆-cycloalkyl can be bound to the respectivesuperordinate general structure via any desired and possible ring memberof the C₃₋₆-cycloalkyl. The C₃₋₆-cycloalkyl can also be condensed withfurther saturated, (partially) unsaturated, (hetero)cyclic, aromatic orheteroaromatic ring systems, i.e. with cycloalkyl, heterocycloalkyl,aryl or heteroaryl residues. Preferred C₃₋₆-cycloalkyls are selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, in particular cyclopropyl.

The terms “C₃₋₇-heterocycloalkyl” mean for the purposes of thisinvention heterocycloaliphatic saturated or unsaturated (but notaromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members, inwhich in each case at least one, if appropriate also two, three or fourcarbon atoms are replaced by a heteroatom or a heteroatom group eachselected independently of one another from the group consisting of O, S,S(═O), S(═O)₂, N, NH and N(C₁₋₆-alkyl) such as N(CH₃), wherein the ringmembers can be unsubstituted or mono- or polysubstituted. TheC₃₋₇-heterocycloalkyl can also be condensed with further saturated,(partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ringsystems, i.e. with cycloalkyl, heterocycloalkyl, aryl or heteroarylresidues. The C₃₋₇-heterocycloalkyl may be bound to the superordinategeneral structure via any possible ring member of the heterocycloalkylif not indicated otherwise.

The term “aryl” for the purpose of this invention represents phenyl,1-naphthyl or 2-naphthyl, wherein the aryl can be unsubstituted or mono-or polysubstituted.

The term “heteroaryl” for the purpose of this invention represents acyclic aromatic residue containing at least 1, if appropriate also 2, 3,4 or 5 heteroatoms, wherein the heteroatoms are each selectedindependently of one another from the group S, N and O and theheteroaryl residue can be unsubstituted or mono- or polysubstituted; inthe case of substitution on the heteroaryl, the substituents can be thesame or different and be in any desired and possible position of theheteroaryl. The binding to the superordinate general structure can becarried out via any desired and possible ring member of the heteroarylresidue if not indicated otherwise. It is preferable for the heteroarylresidue to be selected from the group consisting of benzofuranyl,benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,benzotriazolyl, benzo-oxazolyl, benzooxadiazolyl, quinazolinyl,quinoxalinyl, carbazolyl, quinolinyl, dibenzo-furanyl, dibenzothienyl,furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl,indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl,naphthyridinyl, oxazolyl, oxa-diazolyl, phenazinyl, phenothiazinyl,phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl),pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl,thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl andtriazinyl.

For the purpose of this invention, the term “said aryl or heteroaryl maybe condensed with an aromatic or aliphatic ring to form a bicycle” isunderstood as meaning a bicyclic ring system wherein at least one ringis aromatic and wherein the link to the superordinate general structureis via an atom of aryl or heteroaryl. The bicyclic ring system may befully aromatic (condensation of aryl or heteroaryl with an aromaticring, so an aryl or heteroaryl moiety) or partially aromatic(condensation of aryl or heteroaryl with a non-aromatic ring, so acycloalkyl or heterocycloalkyl moiety).

In connection with non-aromatic moieties such as “alkyl”, “alkoxy”,“cycloalkyl” and “heterocycloalkyl”, in the context of this inventionthe term “substituted” is understood as meaning replacement of ahydrogen radical by a substituent selected from the group consisting of═O, OH, CN, F, Cl, Br, I, SH, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl,(C₂-C₄)-alkinyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-cyanoalkyl,(C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, (C₁-C₄)-haloalkyl,(C₁-C₄)-thiohaloalkyl, (C₁-C₄)-haloalkoxy,(C₁-C₄)-alkyl-S—(C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl,(C₃-C₆)-cycloalkyl-(C₁-C₃)-alkyl, (C₃-C₇)-heterocycloalkyl, NH₂,NH(C₁-C₄)-alkyl, N((C₁-C₄)-alkyl)₂, NHCO(C₁-C₄)-alkyl,NHCOO(C₁-C₄)-alkyl, NH—C(O)NH₂, NHCONH(C₁-C₄)-alkyl,NHCON((C₁-C₄)-alkyl)₂, NH((C₁-C₄)-alkyl)COO(C₁-C₄)-alkyl,NH((C₁-C₄)-alkyl)-CONH₂, NH((C₁-C₄)-alkyl)CONH(C₁-C₄)-alkyl,NH((C₁-C₄)-alkyl)CON((C₁-C₄)-alkyl)₂, NHS(O)₂OH, NHS(O)₂(C₁-C₄)-alkyl,NHS(O)₂O(C₁-C₄)-alkyl, NHS(O)₂NH₂, NHS(O)₂NH(C₁-C₄)-alkyl,NHS(O)₂N((C₁-C₄)-alkyl)₂, NH((C₁-C₄)-alkyl)-S(O)₂OH,NH((C₁-C₄)-alkyl)S(O)₂(C₁-C₄)-alkyl,NH((C₁-C₄)-alkyl)S(O)₂O(C₁-C₄)-alkyl, NH((C₁-C₄)-alkyl)S(O)₂NH₂,NH((C₁-C₄)-alkyl)S(O)₂NH(C₁-C₄)-alkyl, CO₂H, CO(C₁-C₄)-alkyl,COO(C₁-C₄)-alkyl, OCO(C₁-C₄)-alkyl, OCOO(C₁-C₄)-alkyl, CONH₂,CONH(C₁-C₄)-alkyl, CON((C₁-C₄)-alkyl)₂, OCONH(C₁-C₄)-alkyl,OCON((C₁-C₄)-alkyl)₂, OS(O)₂(C₁-C₄)-alkyl, OS(O)₂OH,OS(O)₂(C₁-C₄)-alkyl, OS(O)₂NH₂, OS(O)₂NH(C₁-C₄)-alkyl,OS(O)₂N((C₁-C₄)-alkyl)₂, S(O)(C₁-C₄)-alkyl, S(O)₂(C₁-C₄)-alkyl, S(O)₂OH,S(O)₂O(C₁-C₄)-alkyl, S(O)₂NH₂, S(O)₂NH(C₁-C₄)-alkyl, andS(O)₂N((C₁-C₄)-alkyl)₂. If a moiety is substituted with more than 1substituent, e.g. by 2, 3, 4, or 5 substituents, these substituents maybe present either on different or on the same atoms, e.g. as in the caseof CF₃ or CH₂CF₃, or at different places, as in the case of CH(Cl)CHCl₂.Substitution with more than 1 substituent may include identical ordifferent substituents, such as, for example, in the case ofCH(OH)CHCl₂. Preferably, the substituents may be selected from the groupconsisting of F, Cl, Br, CF₃, CHF₂, CH₂F, OCF₃, OH, CN, (C₁-C₄)-alkyl,(C₁-C₄)-hydroxyalkyl, (C₁-C₄)-alkoxy, (C₃-C₆)-cycloalkyl, NH₂,NH(C₁-C₄)-alkyl, N((C₁-C₄)-alkyl)₂, NHCO(C₁-C₄)-alkyl,NHCONH(C₁-C₄)-alkyl, NHCON((C₁-C₄)-alkyl)₂, NHS(O)₂(C₁-C₄)-alkyl, CONH₂,CONH(C₁-C₄)-alkyl, CON((C₁-C₄)-alkyl)₂, S(O)(C₁-C₄)-alkyl andS(O)₂(C₁-C₄)-alkyl.

In connection with aromatic moieties such as “aryl” and “heteroaryl”, inthe context of this invention the term “substituted” is understood asmeaning replacement of a hydrogen radical by a substituent selected fromthe group consisting of OH, halogen, CN, SH, nitro, (C₁-C₄)-alkyl,(C₂-C₄)-alkenyl, (C₂-C₄)-alkinyl, (C₁-C₄)-hydroxyalkyl,(C₁-C₄)-cyanoalkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl,(C₁-C₄)-haloalkyl, (C₁-C₄)-thiohaloalkyl, (C₁-C₄)-haloalkoxy,(C₁-C₄)-alkyl-S—(C₁-C₄)-alkyl, (C₃-C₆)-Cycloalkyl,(C₃-C₆)-cycloalkyl-(C₁-C₃)-alkyl, (C₃-C₇)-heterocycloalkyl, NH₂,NH(C₁-C₄)-alkyl, N((C₁-C₄)-alkyl)₂, NHCO(C₁-C₄)-alkyl,NHCOO(C₁-C₄)-alkyl, NHC(O)NH₂, NHCONH(C₁-C₄)-alkyl,NHCON((C₁-C₄)-alkyl)₂, NH((C₁-C₄)-alkyl)COO(C₁-C₄)-alkyl,NH((C₁-C₄)-alkyl)CONH₂, NH((C₁-C₄)-alkyl)CONH(C₁-C₄)-alkyl,NH((C₁-C₄)-alkyl)CON((C₁-C₄)-alkyl)₂, NHS(O)₂OH, NHS(O)₂(C₁-C₄)-alkyl,NHS(O)₂O(C₁-C₄)-alkyl, NH—S(O)₂NH₂, NHS(O)₂NH(C₁-C₄)-alkyl,NH—S(O)₂N((C₁-C₄)-alkyl)₂, NH((C₁-C₄)-alkyl)-S(O)₂OH,NH((C₁-C₄)-alkyl)S(O)₂(C₁-C₄)-alkyl,NH((C₁-C₄)-alkyl)-S(O)₂O(C₁-C₄)-alkyl, NH((C₁-C₄)-alkyl)S(O)₂NH₂,NH((C₁-C₄)-alkyl)S(O)₂NH(C₁-C₄)-alkyl, CO₂H, CO(C₁-C₄)-alkyl,COO(C₁-C₄)-alkyl, OCO(C₁-C₄)-alkyl, OCOO(C₁-C₄)-alkyl, CONH₂,CONH(C₁-C₄)-alkyl, CON((C₁-C₄)-alkyl)₂, OCONH(C₁-C₄)-alkyl,OCON((C₁-C₄)-alkyl)₂, OS(O)₂(C₁-C₄)-alkyl, OS(O)₂OH,OS(O)₂(C₁-C₄)-alkoxy, OS(O)₂NH₂, OS(O)₂NH(C₁-C₄)-alkyl,OS(O)₂—N((C₁-C₄)-alkyl)₂, S(O)(C₁-C₄)-alkyl, S(O)₂(C₁-C₄)-alkyl,S(O)₂OH, S(O)₂O(C₁-C₄)-alkyl, S(O)₂NH₂, S(O)₂NH(C₁-C₄)-alkyl, andS(O)₂N((C₁-C₄)-alkyl)₂. If a moiety is substituted with more than 1substituent, e.g. by 2, 3, 4, or 5 substituents, these substituents maybe identical or different. Preferably, the substituents may be selectedfrom the group consisting of F, Cl, Br, CF₃, CHF₂, CH₂F, OCF₃, OH, CN,(C₁-C₄)-alkyl, (C₁-C₄)-hydroxyalkyl, (C₁-C₄)-alkoxy, (C₃-C₆)-cycloalkyl,NH₂, NH(C₁-C₄)-alkyl, N((C₁-C₄)-alkyl)₂, NHCO(C₁-C₄)-alkyl,NHCONH(C₁-C₄)-alkyl, NHCON((C₁-C₄)-alkyl)₂, NHS(O)₂(C₁-C₄)-alkyl, CONH₂,CONH(C₁-C₄)-alkyl, CON((C₁-C₄)-alkyl)₂, S(O)(C₁-C₄)-alkyl andS(O)₂(C₁-C₄)-alkyl.

Within the scope of the present invention, the symbol

used in the formulae denotes a link of a corresponding residue to therespective superordinate general structure.

In one embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that Y representsO.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R^(3a)represents H.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that

-   Z represents N(R^(3b)), wherein R^(3b) represents H; or-   Z represents C(R^(4a)R^(4b)), wherein R^(4a) represents CH₃ and    R^(4b) represents H or wherein R^(4a) and R^(4b) each represent H.

In a preferred embodiment of the invention, Z representsC(R^(4a)R^(4b)), wherein R^(4a) represents CH₃ and R^(4b) represents H,therefore being in one enantiomeric form.

Preferably, Z represents C(R^(4a)R^(4b)), wherein R^(4a) represents CH₃and R^(4b) represents H, and the carbon atom bearing the residues R^(4a)and R^(4b) has the (R)-configuration or has the (S)-configuration:

More preferably, the compound according to general formula (I) ischaracterized in that

-   Z represents N(R^(3b)), wherein R^(3b) represents H.

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that R²represents CH₃, CFH₂, CHF₂, CF₃, CH₂CH₃, CH(CH₃)₂ or C(CH₃)₃.

In a preferred embodiment of the invention, the compound according togeneral formula (I) is characterized in that R² represents CF₃ orC(CH₃)₃.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in that

-   R¹ represents

wherein

-   n is 0, 1, 2 or 3;-   R⁵ represents F, Cl, Br, CN, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,    halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,    hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy    and-   each R⁶ independently is selected from the group consisting of F,    Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,    cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,    halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy,    C₁₋₄-alkylS(O), hydroxy-C₁₋₄-alkylS(O), C₁₋₄-alkylS(O)₂,    hydroxy-C₁₋₄-alkylS(O)₂, H₂N, (C₁₋₄-alkyl)(H)N,    (hydroxy-C₁₋₄-alkyl)(H)N, (C₁₋₄-alkyl)₂N,    (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (hydroxy-C₁₋₄-alkyl)₂N,    [(C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),    [(hydroxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),    [(C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),    [(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl), H₂NC(O),    (C₁₋₄-alkyl)(H)NC(O), (hydroxy-C₁₋₄-alkyl)(H)NC(O),    (C₁₋₄-alkyl)₂NC(O), (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),    (hydroxy-C₁₋₄-alkyl)₂N—C(O), H₂NS(O)₂ (C₁₋₄-alkyl)(H)NS(O)₂,    (hydroxy-C₁₋₄-alkyl)(H)N—S(O)₂, (C₁₋₄-alkyl)₂NS(O)₂,    (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂, (hydroxy-C₁₋₄-alkyl)₂NS(O)₂,    C₃₋₆-cycloalkyl, (C₃₋₆-cycloalkyl)-C₁₋₄-alkyl,    (C₃₋₆-cycloalkyl)-C₁₋₄-alkoxy, C₃₋₇-heterocycloalkyl,    (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkyl,    (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkoxy,    -   wherein said C₃₋₆-cycloalkyl or C₃₋₇-heterocycloalkyl may be        unsubstituted or mono- or independently polysubstituted by one        or more substituents, selected from H, F, Cl, Br, CN, OH, ═O,        C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,        cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,        halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy;    -   aryl, heteroaryl, (aryl)C₁₋₄-alkyl or (heteroaryl)C₁₋₄-alkyl,    -   wherein said aryl or heteroaryl may be unsubstituted or mono- or        independently polysubstituted by one or more substituents,        selected from the group consisting of H, F, Cl, Br, CN, OH,        C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,        cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,        halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy.

Preferably,

-   R¹ is selected from the group consisting of

Particularly preferably, R¹ represents

Even more preferably, R¹ represents

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in thatthe compound of general formula (I) has general formula (Ia)

wherein

-   X represents O or S;-   Z represents N(R^(3b)) or C(R^(4a)R^(4b));-   n is 0, 1 or 2;-   R² represents CH₃, CFH₂, CHF₂, CF₃, CH₂CH₃, CH(CH₃)₂ or C(CH₃)₃,-   R^(3b) represents H, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,    halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl or C₁₋₄-alkoxy-C₁₋₄-alkyl;-   R^(4a) and R^(4b) each independently represent H, F, Cl or    C₁₋₄-alkyl;-   R⁵ represents F, Cl, Br, CN, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,    halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,    hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, and C₁₋₄-alkoxy-C₁₋₄-alkoxy;-   each R⁶ independently is selected from the group consisting of F,    Cl, Br, CN, OH, C₁₋₄-alkyl, CF₃, hydroxy-C₁₋₄-alkyl,    halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,    hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy,    C₁₋₄-alkoxy-C₁₋₄-alkoxy, C₁₋₄-alkylS(O), C₁₋₄-alkylS(O)₂, H₂N,    (C₁₋₄-alkyl)(H)N, (C₁₋₄-alkyl)₂N, H₂NC(O), (C₁₋₄-alkyl)(H)NC(O) and    (C₁₋₄-alkyl)₂NC(O);    and-   Ar represents aryl or heteroaryl,    -   wherein said aryl or heteroaryl may be condensed with an        aromatic or aliphatic ring to form a bicycle,    -   and wherein said aryl or heteroaryl and said condensed aromatic        or aliphatic ring each independently may be unsubstituted or        mono- or independently polysubstituted by one or more        substituents, selected from the group consisting of F, Cl, Br,        CN, OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,        cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,        halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy,        hydroxy-C₁₋₄-alkoxy-C₁₋₄-alkyl, C₁₋₄-alkylS(O),        hydroxy-C₁₋₄-alkylS(O), halo-C₁₋₄-alkylS(O),        cyano-C₁₋₄-alkylS(O), C₁₋₄-alkoxy-C₁₋₄-alkylS(O),        C₁₋₄-alkylS(O)₂, hydroxy-C₁₋₄-alkylS(O)₂, halo-C₁₋₄-alkylS(O)₂,        cyano-C₁₋₄-alkylS(O)₂, C₁₋₄-alkoxy-C₁₋₄-alkylS(O)₂,        C₁₋₄-alkylS(O)C₁₋₄-alkyl, hydroxy-C₁₋₄-alkylS(O)C₁₋₄-alkyl,        C₁₋₄-alkylS(O)₂C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl-S(O)₂C₁₋₄-alkyl,        H₂N, (C₁₋₄-alkyl)(H)N, (hydroxy-C₁₋₄-alkyl)(H)N,        (halo-C₁₋₄-alkyl)(H)N, (cyano-C₁₋₄-alkyl)(H)N,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N, (C₃₋₆-cycloalkyl)(H)N,        (C₃₋₇-heterocycloalkyl)(H)N, (C₁₋₄-alkyl)₂N,        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N,        (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N, (hydroxy-C₁₋₄-alkyl)₂N,        (C₃₋₆-cyclo-alkyl)(hydroxy-C₁₋₄-alkyl)N,        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N, (H)₂NC₁₋₄-alkyl,        [(C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(hydroxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(halo-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(cyano-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),        [(C₃₋₆-cycloalkyl)(H)N](C₁₋₄-alkyl),        [(C₃₋₇-heterocycloalkyl)(H)N](C₁₋₄-alkyl),        [(C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),        [(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(hydroxy-C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),        [(C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl),        [(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl),        H₂NC(O), (C₁₋₄-alkyl)(H)NC(O), (hydroxy-C₁₋₄-alkyl)(H)NC(O),        (halo-C₁₋₄-alkyl)(H)NC(O), (cyano-C₁₋₄-alkyl)(H)NC(O),        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)NC(O), (C₃₋₆-cyclo-alkyl)(H)NC(O),        (C₃₋₇-heterocycloalkyl)(H)NC(O), (C₁₋₄-alkyl)₂NC(O),        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O),        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NC(O),        (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)NC(O),        (hydroxy-C₁₋₄-alkyl)₂NC(O),        (C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(O),        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(O), H₂NS(O)₂,        (C₁₋₄-alkyl)(H)NS(O)₂, (hydroxy-C₁₋₄-alkyl)(H)NS(O)₂,        (halo-C₁₋₄-alkyl)(H)NS(O)₂, (cyano-C₁₋₄-alkyl)(H)NS(O)₂,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)—NS(O)₂, (C₃₋₆-cycloalkyl)(H)N S(O)₂,        (C₃₋₇-heterocycloalkyl)(H)NS(O)₂, (C₁₋₄-alkyl)₂NS(O)₂,        (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(O)₂,        (C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NS(O)₂,        (C₃₋₇-hetero-cycloalkyl)(C₁₋₄-alkyl)NS(O)₂,        (hydroxy-C₁₋₄-alkyl)₂NS(O)₂,        (C₃₋₆-cycloalkyl)-(hydroxy-C₁₋₄-alkyl)NS(O)₂,        (C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NS(O)₂,        H₂NS(O)₂N(H)C₁₋₄-alkyl, (C₁₋₄-alkyl)(H)NS(O)₂N(H)C₁₋₄-alkyl,        (hydroxy-C₁₋₄-alkyl)(H)NS(O)₂N(H)C₁₋₄-alkyl,        (C₁₋₄-alkyl)₂NS(O)₂N(H)C₁₋₄-alkyl,        (C₁₋₄-alkyl)S(O)₂N(H)C₁₋₄-alkyl,        (hydroxy-C₁₋₄-alkyl)S(O)₂N(H)C₁₋₄-alkyl, C₃₋₆-cycloalkyl,        (C₃₋₆-cycloalkyl)-C₁₋₄-alkyl, (C₃₋₆-cycloalkyl)-C₁₋₄-alkoxy,        C₃₋₇-heterocycloalkyl, (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkyl,        (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkoxy,        -   wherein said C₃₋₆-cycloalkyl or C₃₋₇-heterocycloalkyl may be            unsubstituted or mono- or independently polysubstituted by            one or more substituents, selected from H, F, Cl, Br, CN,            OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,            cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,            hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and            C₁₋₄-alkoxy-C₁₋₄-alkoxy;    -   aryl, heteroaryl, (aryl)C₁₋₄-alkyl or (heteroaryl)C₁₋₄-alkyl,        -   wherein said aryl or heteroaryl may be unsubstituted or            mono- or independently polysubstituted by one or more            substituents, selected from the group consisting of H, F,            Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,            halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,            hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and            C₁₋₄-alkoxy-C₁₋₄-alkoxy;            optionally in the form of a single stereoisomer or a mixture            of stereoisomers, in the form of the free compound and/or a            physiologically acceptable salt or a solvate thereof.

In one preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) or according to generalformula (Ia) is characterized in that X is O.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) or according to generalformula (Ia) is characterized in that X is S.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in thatthe compound has general formula (Ia), wherein n is 0.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in thatthe compound has general formula (Ia), wherein R⁵ is F, Cl, CN, CH₃,CHF₂, CF₃, CH₂CH₃, OCH₃, OCF₃, OCHF₂ or CH₂OCH₃.

Preferably, the compound according to general formula (I) ischaracterized in that the compound has general formula (Ia), wherein R⁵is F, Cl, CN, CH₃, CHF₂, CF₃, CH₂CH₃, OCH₃, OCF₃, OCHF₂ or CH₂OCH₃ and nis 0.

In yet another embodiment of the first aspect of the invention, thecompound according to general formula (I) or general formula (Ia) ischaracterized in that

Ar is selected from phenyl or pyridinyl,wherein said phenyl or pyridinyl may be condensed with an aromatic oraliphatic ring to form a bicycle,and wherein said phenyl or pyridinyl and said condensed aromatic oraliphatic ring each independently may be unsubstituted or mono- orindependently polysubstituted by one or more substituents, selected fromthe group consisting of F, Cl, Br, CN, OH, ═O, C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy, H₂N,(C₁₋₄-alkyl)(H)N, (hydroxy-C₁₋₄-alkyl)(H)N, H₂NC(O),(C₁₋₄-alkyl)(H)NC(O), (hydroxy-C₁₋₄-alkyl)(H)NC(O), (C₁₋₄-alkyl)₂NC(O),(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(O) and C₃₋₆-cycloalkyl.

In a preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) or general formula (Ia) ischaracterized in that Ar is selected from phenyl or pyridinyl, whereinsaid phenyl or said pyridinyl is condensed with an aromatic or aliphaticring to form a bicycle.

Preferably, the compound according to general formula (I) or generalformula (Ia) is characterized in that

Ar is selected from

each unsubstituted or mono- or independently polysubstituted by one ormore substituents, wherein said substituent(s) are selected from thegroup consisting of F, Cl, Br, CN, ═O, OH, CH₃, CHF₂, CF₃, CH₂CH₃,(CH₂)₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃,OCH₃, OCF₃, OCHF₂, CH₂OCH₃, CH₂OCF₃, CH₂OH, CH₂CH₂OH, OCH₂CH₂OH,N(H)CH₂CH₂OH, N(CH₃)CH₂CH₂OH, CH₂OCH₂CH₂OH, CH₂N(H)CH₂CH₂OH,CH₂N(CH₃)CH₂CH₂OH, CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂N(H)CH₃, CH₂N(H)S(O)₂NH₂,CH₂N(H)S(O)₂CH₃,

In a preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) or general formula (Ia) ischaracterized in that Ar is selected from 1-naphthyl, 2-naphthyl,5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 5-isoquinolinyl,6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl, 5-quinoxalinyl,6-quinoxalinyl, 5-phthalazinyl, 6-phthalazinyl, 5-quinazolinyl,6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 5-cinnolinyl,6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 5-indazolyl,5-(1-methyl)-indazolyl, 4-indazolyl, 4-(1-methyl)-indazolyl,1-(5,6,7,8-tetrahydro)-naphthyl, 2-(5,6,7,8-tetrahydro)-naphthyl,4-(2,3-dihydro)-1H-indenyl, 5-(2,3-dihydro)-1H-indenyl,4-benzo[d][1,3]dioxolyl, 5-benzo[d][1,3]dioxolyl,5-(2,3-dihydro)-benzo[b][1,4]dioxinyl,6-(2,3-dihydro)-benzo[b][1,4]dioxinyl.

In a preferred embodiment of the first aspect of the invention, thecompound according to general formula (I) or general formula (Ia) ischaracterized in that Ar is selected from

wherein G is CH or CF.

Particularly preferred are compounds according to the invention from thegroup

1N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluoro-EX-01 4-(2-hydroxyethyl)phenyl)-propanamide 2N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3-fluoro-EX-02 4-(2-hydroxyethyl)-phenyl)propanamide 3N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-EX-03 (methylsulfonamido-methyl)phenyl)propanamide 4N-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4- EX-04(methylsulfonamidomethyl)phenyl)propanamide 5N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-EX-05 ((sulfamoylamino)methyl)-phenyl)propanamide 6N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-EX-06 ((sulfamoylamino)methyl)-phenyl)propanamide 7N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-EX-07 (hydroxymethyl)phenyl)propanamide 8N-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4- EX-08(hydroxymethyl)phenyl)propanamide 9N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-(3-EX-09 hydroxyoxetan-3-yl)phenyl)propanamide 10N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-(3-EX-10 hydroxyoxetan-3-yl)phenyl)propanamide 11N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluoro-EX-11 6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide 12N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-fluoro-EX-12 6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide 13N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-EX-13 hydroxyethyl)amino)pyridin-3-yl)propanamide 14N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-EX-14 hydroxyethyl)amino)pyridin-3-yl)propanamide 15N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-EX-15 hydroxyethyl)amino)pyridin-3-yl)propanamide (enantiomer 1) 16N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-EX-16 hydroxyethyl)amino)pyridin-3-yl)propanamide (enantiomer 2) 17N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-EX-17 hydroxyethyl)amino)pyridin-3-yl)propanamide (nenatiomer 1) 18N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-EX-18 hydroxyethyl)amino)pyridin-3-yl)propanamide (enantiomer 2) 19N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluoro-EX-19 6-(hydroxymethyl)pyridin-3-yl)propanamide 20N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-fluoro-EX-20 6-(hydroxymethyl)pyridin-3-yl)propanamide (enantiomer 1) 21N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluoro-EX-21 6-(hydroxymethyl)pyridin-3-yl)propanamide 22N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluoro-EX-22 6-(hydroxymethyl)pyridin-3-yl)propanamide (enantiomer 2) 23N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3-fluoro-EX-23 4-((sulfamoylamino)methyl)phenyl)propanamide 24N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluoro-EX-24 4-((sulfamoylamino)methyl)phenyl)propanamide 251-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6- EX-25(hydroxymethyl)pyridin-3-yl)urea 261-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6- EX-26(hydroxymethyl)pyridin-3-yl)urea 271-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-EX-27 (hydroxymethyl)pyridin-3-yl)urea 281-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-EX-28 (hydroxymethyl)pyridin-3-yl)urea 291-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2- EX-29methoxypyrimidin-5-yl)urea 301-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-EX-30 (methylsulfonyl)ethyl)pyridin-3-yl)urea 311-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-EX-31 (methylsulfonyl)ethyl)pyridin-3-yl)urea 321-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(3-EX-32 hydroxyazetidin-1-yl)pyridin-3-yl)urea 331-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(3-EX-33 hydroxyazetidin-1-yl)pyridin-3-yl)urea 341-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-EX-34 hydroxyethyl)pyridin-3-yl)urea 351-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2- EX-35hydroxyethyl)pyridin-3-yl)urea 361-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2- EX-36hydroxyethyl)pyridin-3-yl)urea 371-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-EX-37 hydroxyethyl)pyridin-3-yl)urea 38N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5- EX-38yl)methyl)ureido)benzyl)methanesulfonamide 39N-(4-(3-((2-(tert-butyl)-4-(3-fluorophenyl)thiazol-5- EX-39yl)methyl)ureido)benzyl)methanesulfonamide 401-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2- EX-40hydroxyethoxy)pyridin-3-yl)urea 411-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2- EX-41hydroxyethoxy)pyridin-3-yl)urea 421-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-EX-42 hydroxyethoxy)pyridin-3-yl)urea 431-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-EX-43 hydroxyethoxy)pyridin-3-yl)urea 44N-((5-(3-chlorophenyl)-2-(tertbutyl)oxazol-4-yl)methyl)-N′-(4- EX-44((sulfamoylamino)methyl)phenyl)urea 45N-((5-(3-chlorophenyl)-2-(tertbutyl)thiazol-5-yl)methyl)-N′-(4- EX-45((sulfamoylamino)methyl)phenyl)urea 461-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2- EX-46hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride 471-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-((2-EX-47 hydroxyethoxy)-methyl)pyridin-3-yl)urea dihydrochloride 481-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-((2-EX-48 hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride 491-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-((2-EX-49 hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride 501-(benzo[d][1,3]dioxol-5-yl)-3-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-EX-50 yl)methyl)urea 511-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydro-1H-EX-51 inden-4-yl)urea 521-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoquinolin-6-EX-52 yl)urea 531-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(quinolin-5-EX-53 yl)urea 541-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3- EX-54dihydrobenzo[b][1,4]dioxin-6-yl)urea 551-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydro-1H-EX-55 inden-5-yl)urea 561-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoquinolin-5-EX-56 yl)urea 57N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)ureido)-2-EX-57 fluorobenzyl)methanesulfonamide 58N-(4-(3-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)ureido)-2- EX-58fluorobenzyl)methanesulfonamide 591-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-fluoro-4-EX-59 (hydroxymethyl)phenyl)urea 601-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-3-(3-fluoro-4- EX-60(hydroxymethyl)phenyl)urea 611-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3- EX-61methoxypyridin-4-yl)urea 621-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyrimidin-5-EX-62 yl)urea 631-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(5- EX-63methylpyridin-2-yl)urea 641-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-4-EX-64 yl)urea 651-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-2-EX-65 yl)urea 661-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-3-EX-66 yl)urea 671-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3- EX-67methylpyridin-4-yl)urea 681-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2- EX-68methylpyridin-4-yl)urea 691-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-fluoropyridin-EX-69 3-yl)urea 701-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6- EX-70methylpyridin-3-yl)urea 711-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2- EX-71methylpyrimidin-5-yl)ureain the form of the free compound and/or a physiologically acceptablesalt thereof.

Furthermore, preference may be given to compounds according to the firstaspect of the invention that cause a 50% displacement of capsaicin,which is present at a concentration of 100 nM, in a FLIPR assay with CHOK1 cells which were transfected with the human VR1 gene at aconcentration of less than 2 000 nM, preferably less than 1 000 nM,particularly preferably less than 300 nM, most particularly preferablyless than 100 nM, even more preferably less than 75 nM, additionallypreferably less than 50 nM, most preferably less than 10 nM. In theprocess, the Ca²⁺ influx is quantified in the FLIPR assay with the aidof a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes Europe BV,Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR,Molecular Devices, Sunnyvale, USA), as described hereinafter.

The compounds according to the first aspect of the invention andcorresponding stereoisomers and also the respective corresponding acids,bases, salts and solvates are toxicologically safe and are thereforesuitable as pharmaceutical active ingredients in pharmaceuticalcompositions.

In second aspect of the invention, the invention therefore furtherrelates to a pharmaceutical composition containing at least one compoundaccording to the first aspect of the invention, in each case ifappropriate in the form of one of its pure stereoisomers, in particularenantiomers or diastereomers, its racemates or in the form of a mixtureof stereoisomers, in particular the enantiomers and/or diastereomers, inany desired mixing ratio, or respectively in the form of a correspondingsalt, or respectively in the form of a corresponding solvate, and alsoif appropriate one or more pharmaceutically compatible auxiliaries.

These pharmaceutical compositions according to the invention aresuitable in particular for vanilloid receptor 1-(VR1/TRPV1) regulation,preferably for vanilloid receptor 1-(VR1/TRPV1) inhibition and/or forvanilloid receptor 1-(VR1/TRPV1) stimulation, i.e. they exert anagonistic or antagonistic effect. Likewise, the pharmaceuticalcompositions according to the invention are preferably suitable for theprophylaxis and/or treatment of disorders or diseases which aremediated, at least in part, by vanilloid receptors 1. The pharmaceuticalcomposition according to the invention is suitable for administration toadults and children, including toddlers and babies. The pharmaceuticalcomposition according to the invention may be found as a liquid,semisolid or solid pharmaceutical form, for example in the form ofinjection solutions, drops, juices, syrups, sprays, suspensions,tablets, patches, capsules, plasters, suppositories, ointments, creams,lotions, gels, emulsions, aerosols or in multiparticulate form, forexample in the form of pellets or granules, if appropriate pressed intotablets, decanted in capsules or suspended in a liquid, and also beadministered as much.

In a preferred embodiment of the second aspect of the invention, thepharmaceutical composition according to the invention is suitable forthe treatment and/or prophylaxis of pain, preferably of pain selectedfrom the group consisting of acute pain, chronic pain, neuropathic painand visceral pain.

In a third aspect of the invention, the present invention furtherrelates to a compound according to the first aspect of the invention foruse in vanilloid receptor 1-(VR1/TRPV1) regulation, preferably for usein vanilloid receptor 1-(VR1/TRPV1) inhibition and/or vanilloid receptor1-(VR1/TRPV1) stimulation.

The present invention therefore further relates to a compound accordingto the first aspect of the invention and also for use in the prophylaxisand/or treatment of disorders and/or diseases which are mediated, atleast in part, by vanilloid receptors 1.

In particular, the present invention therefore further relates to acompound according to the first aspect of the invention for use in theprophylaxis and/or treatment of disorders and/or diseases selected fromthe group consisting of pain, preferably pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain, visceral painand joint pain; hyperalgesia; allodynia; causalgia; migraine;depression; nervous affection; axonal injuries; neurodegenerativediseases, preferably selected from the group consisting of multiplesclerosis, Alzheimer's disease, Parkinson's disease and Huntington'sdisease; cognitive dysfunctions, preferably cognitive deficiency states,particularly preferably memory disorders; epilepsy; respiratorydiseases, preferably selected from the group consisting of asthma,bronchitis and pulmonary inflammation; coughs; urinary incontinence;overactive bladder (OAB); disorders and/or injuries of thegastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowelsyndrome; strokes; eye irritations; skin irritations; neurotic skindiseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex;inflammations, preferably inflammations of the intestine, the eyes, thebladder, the skin or the nasal mucous membrane; diarrhoea; pruritus;osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eatingdisorders, preferably selected from the group consisting of bulimia,cachexia, anorexia and obesity; medication dependency; misuse ofmedication; withdrawal symptoms in medication dependency; development oftolerance to medication, preferably to natural or synthetic opioids;drug dependency; misuse of drugs; withdrawal symptoms in drugdependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency; for diuresis; for antinatriuresis; forinfluencing the cardiovascular system; for increasing vigilance; for thetreatment of wounds and/or burns; for the treatment of severed nerves;for increasing libido; for modulating movement activity; for anxiolysis;for local anaesthesia and/or for inhibiting undesirable side effects,preferably selected from the group consisting of hyperthermia,hypertension and bronchoconstriction, triggered by the administration ofvanilloid receptor 1 (VR1/TRPV1 receptor) agonists.

A preferred embodiment of the third aspect of the invention is acompound according to the first aspect of the invention for use in theprophylaxis and/or treatment of pain, preferably of pain selected fromthe group consisting of acute pain, chronic pain, neuropathic pain andvisceral pain.

In a fourth aspect of the invention, the present invention furtherrelates to the use of at least one compound according to the firstaspect of the present invention for the preparation of a pharmaceuticalcomposition for the prophylaxis and/or treatment of disorders and/ordiseases which are mediated, at least in part, by vanilloid receptors 1.

A fifth aspect of the present invention is a method for vanilloidreceptor 1-(VR1/TRPV1) regulation, preferably for vanilloid receptor1-(VR1/TRPV1) inhibition and/or for vanilloid receptor 1-(VR1/TRPV1)stimulation, and, further, a method of treatment and/or prophylaxis ofdisorders and/or diseases, which are mediated, at least in part, byvanilloid receptors 1, in a mammal, which comprises administering aneffective amount of at least one compound according to the first aspectof the invention to the mammal.

A preferred embodiment of the fifth aspect of the invention is hence amethod of treatment and/or prophylaxis of pain, preferably of painselected from the group consisting of acute pain, chronic pain,neuropathic pain, visceral pain and joint pain, which comprisesadministering an effective amount of at least one compound according tothe first aspect of the invention to the mammal.

The effectiveness against pain can be shown, for example, in the Bennettor Chung model (Bennett, G. J. and Xie, Y. K., Pain 1988, 33(1), 87-107;Kim, S. H. and Chung, J. M., Pain 1992, 50(3), 355-363), by tail flickexperiments (e.g. D'Amour und Smith, J. Pharm. Exp. Ther. 1941, 72,74-79) or by the formalin test (e.g. D. Dubuisson et al., Pain 1977, 4,161-174).

EXAMPLES

The indication “equivalents” (“eq.” or “eq” or “equiv.” or “equiv”)means molar equivalents, “RT” or “rt” means room temperature (23±7° C.),“M” are indications of concentration in mol/l, “aq.” means aqueous,“sol.” means solution.

Further abbreviations: conc.: concentrated; DBU:1,8-Diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane;DIBAL:diisobylaluminiumhydride; DMAP: 4-dimethyaminopyridine; DMS:dimethylsulfide; DMF: dimethylformamide; DPPA: diphenylphosphoryl azide;EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et₂O:diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h: hour(s); HOBt:hydroxybenzotriazole; KO^(t)Bu: potassium tert.-butanolate; LAH: lithiumaluminium hydride; MeOH: methanol; MCPBA:m-chloroperbenzoic acid; min:minutes; PE: petroleum ether; PPh₃: triphenylphosphine; RM: reactionmixture; sat.: saturated; TBDMSCl: tert-butyldimethylsilylchloirde; TEA:triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC:thin layer chromatography.

The yields of the compounds prepared were not optimized. Alltemperatures are uncorrected. All starting materials which are notexplicitly described were either commercially available (the details ofsuppliers such as for example Acros, Avocado, Aldrich, Apollo, Bachem,Fluka, FluoroChem, Lancaster, Manchester Organics, MatrixScientific,Maybridge, Merck, Rovathin, Sigma, TCI, Oakwood, etc. can be found inthe Symyx® Available Chemicals Database of MDL, San Ramon, US or theSciFinder® Database of the ACS, Washington D.C., US, respectively, forexample) or the synthesis thereof has already been described preciselyin the specialist literature (experimental guidelines can be found inthe Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder®Database of the ACS, Washington D.C., US, respectively, for example) orcan be prepared using the conventional methods known to the personskilled in the art.

The stationary phase used for the column chromatography was silica gel60 (0.04-0.063 mm) from E. Merck, Darmstadt. The mixing ratios ofsolvents or eluents for chromatography are specified in v/v. All theintermediate products and exemplary compounds were analyticallycharacterized by means of ¹H-NMR spectroscopy. In addition, massspectrometry tests (MS, m/z for [M+H]⁺) were carried out for all theexemplary compounds and selected intermediate products.

Synthesis of Exemplary Compounds

In general, the 5-methylamino azoles INT-10 can be synthesized accordingto Scheme 1. In brief, thioamides INT-2a,b required for thiazolesynthesis can be prepared by reacting the corresponding amides INT-1a,bwith Lawesson's reagent.

Phenylethanone (INT-3) is reacted with dimethyl carbonate (4) to yield3-oxopropanoates (INT-5). Oxidation of INT-5 with Dess-Martinperiodinane in the presence of p-TsOH gives rise to methyl3-oxo-2-(tosyloxy)propanoates (INT-6). Reaction of INT-6 with the amidesINT-1 or thioamides INT-2 resulted in the oxazoles INT-7a,b-i andthiazoles INT-7-ab-ii, respectively. Reduction of the various INT-7 withLiAlH₄ yields the alcohols INT-8, which can be converted to the azidesINT-9. Finally, Staudinger reduction with TPP in aqueous THF yields the5-methylamino azoles INT-10, which were isolated as theirhydrochlorides.

Synthesis Azole Methylamine Hydrochlorides INT-10 Synthesis of(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanamine hydrochloride(INT-10a-ii) Synthesis of 2,2-dimethylpropanethioamide (INT-2a)

To a stirred solution of pivalamide (INT-1a, 5.0 g, 49.43 mmol, 1.0 eq)in THF (150 mL) was added Lawesson's reagents (29.9 g, 74.1 mmol, 1.5eq) and the RM was stirred at 70° C. for 4 h. The RM was concentrated,diluted with Et₂O (30 mL) and washed with NaHCO₃ solution (30 mL), theorganic layer was dried over MgSO₄ and concentrated under reducedpressure. The crude was washed with hexane (25 mL) to get2,2-dimethylpropanethioamide (INT-2a, 4.0 g, 70%) which was used withoutfurther purification. TLC system: EtOAc/PE (7:3), R_(f): 0.6

Synthesis of methyl 3-(3-chlorophenyl)-3-oxopropanoate (INT-5a)

To a stirred suspension of NaH (170 mg, 7.11 mmol, 1.1 eq) in THF (30mL) at 0° C. was added 1-(3-chlorophenyl)ethanone (INT-3a, 1.00 g, 6.46mmol, 1.0 eq) followed by dimethyl carbonate (4, 1.17 g, 12.9 mmol, 2.0eq) and the RM was heated to reflux for 3 h. The RM was quenched withwater (10 ml) and extracted with EtOAC (20 mL), the organic layer wasdried over Na₂SO₄ filtered and evaporated to get methyl3-(3-chlorophenyl)-3-oxopropanoate (INT-5a, 700 mg, 73%) which was usedwithout further purification. TLC system: EtOAc/PE (3:2)

Synthesis of methyl 3-(3-chlorophenyl)-3-oxo-2-(tosyloxy)propanoate(INT-6a)

To a stirred solution of DMP (6.2 g, 14.1 mmol, 1.5 eq) in ACN (20 mL)was added p-TsOH (3.57 g, 18.8 mmol, 2.0 eq) followed by methyl3-(3-chlorophenyl)-3-oxopropanoate (5, 2.0 g, 9.4 mmol, 1.0 eq) and theRM heated to reflux for 6 h. The RM was filtered, the filtrate wasdiluted with water (50 mL) and extracted with EtOAc (70 mL). The organiclayer was washed with NaHCO₃ solution(30 mL), dried over anhydrousNa₂SO₄, concentrated and the resulting crude was purified by silica gel(100-200 mesh) column chromatography using EtOAc/PE (1:9) as an eluentto get methyl 3-(3-chlorophenyl)-3-oxo-2-(tosyloxy)propanoate (INT-6a,1.0 g, 28%). TLC system: EtOAc/PE (2:3), R_(f): 0.55

Synthesis of methyl2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii)

To a stirred solution of methyl 3-(3-chlorophenyl)-3-oxo-2-(tosyloxy)(INT-6, 1.0 g, 2.6 mmol, 1.0 eq) in MeOH (10 mL) was2,2-dimethylpropanethioamide (INT-2a, 0.367 g, 3.1 mmol, 1.2 eq) and theRM was heated to reflux for 16 h. The RM was concentrated under reducedpressure and the crude was purified by silica gel (100-200 mesh) columnchromatography using EtOAc/PE (1:9) as eluent to get methyl2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii,0.450 g, 55%). TLC system: PE (2:3), R_(f): 0.55

Synthesis of (2-(tert-butyl)-4-(3-chlorophenyl) thiazol-5-yl)methanol(INT-8a-ii)

To a stirred solution of methyl2-(tert-butyl)-4-(3-chlorophenyl)thiazole-5-carboxylate (INT-7a-ii, 450mg, 1.4 mmol, 1.0 eq) in THF (10 mL) was added LiAlH₄ (0.055 g, 1.4mmol, 1.0 eq) at 0° C. and the RM was stirred at same temperature for 2h. The RM was quenched with MeOH (2 mL), filtered through a pad ofcelite and concentrated under reduced to get(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanol (INT-8a-ii, 400mg, 90%) as colorless liquid which was used without furtherpurification. TLC system: EtOAc/PE (2:3), R_(f): 0.4

Synthesis of 5-(azidomethyl)-2-(tert-butyl)-4-(3-chlorophenyl)thiazole(INT-9a-ii)

To a stirred solution of(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanol (INT-8a-ii, 400mg, 1.36 mmol, 1.0 eq) in THF (10 mL) was added DBU (620 mg, 4.08 mmol,3.0 eq) followed by DPPA (748 mg, 2.72 mmol, 2.0 eq) and the RM wasstirred at RT for 16 h. The RM was concentrated and diluted with EtOAc(20 mL), washed with water (30 mL), dried over Na₂SO₄ and concentratedunder reduced pressure. The crude was purified by silica gel columnchromatography (100-200 mesh) using EtOAc/PE (1:9) as eluent to get5-(azidomethyl)-2-(tert-butyl)-4-(3-chlorophenyl)thiazole (INT-9a-ii,400 mg, 90%) as yellow liquid. TLC system: EtOAc/PE (2:8), R_(f): 0.6

Synthesis (2-(tert-butyl)-4-(3-chlorophenyl) thiazol-5-yl)methanaminehydrochloride (INT-10a-ii)

To a stirred solution of5-(azidomethyl)-2-(tert-butyl)-4-(3-chlorophenyl)thiazole (INT-9a-ii,400 mg, 1.3 mmol, 1.0 eq) in THF (10 mL) was added TPP (685 mg, 2.6mmol, 2.0 eq) followed by water (1.0 mL) and the RM was stirred at RTfor 16 h. The RM was concentrated and the resulting crude was dissolvedin toluene (10 mL) and extracted with 2N HCl (2×10 mL). The aqueouslayer was basified with 2N NaOH and extracted with ether (3×10 mL). Theorganic layers were dried over Na₂SO₄ and HCl in ether was added to get(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methanamine hydrochloride(INT-10a-ii, 300 mg, 80%) as a white solid. TLC system: MeOH/DCM (1:9),R_(f): 0.4

The following azole methylamine hydrochlorides INT-10 were preparedaccording to the procedure described above.

TABLE 1 List of INT-10 prepared according to the procedure described forINT-10a-ii. (2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5- INT-10a-i UsingINT-1a yl)methanamine hydrochloride instead of INT-2a(4-(3-chlorophenyl)-2-(trifluorometh- INT-10b-i Using INT-1byl)oxazol-5- instead of yl)methanamine hydrochloride INT-2a(4-(3-chlorophenyl)-2-(trifluorometh- INT-10b-ii Using INT-2byl)thiazol-5- instead of yl)methanamine hydrochloride INT-2a(2-(tert-butyl)-4-(m-tolyl)thiazol-5- INT-10a-iii Using INT-3byl)methanaminium chloride instead of INT-3a(2-(tert-butyl)-4-(3-fluorophenyl)thiazol-5- INT-10a-iv Using INT-3cyl)methanaminium chloride instead of INT-3a

Hydrochlorides INT-10 could be converted to the azole amides by couplingwith the acids INT-11 in the presence of EDCI.HCl (Scheme 2).

The acids INT-10 used in this invention are summarized in Table 2.

TABLE 2 List of acids 2-(3-fluoro-4-(2-hydroxyethyl)phe- INT-11aSynthesis see below nyl)propanoic acid 2-(3-fluoro-4- INT-11bSynthesized as (methylsulfonamidomethyl)phe- described in nyl)propanoicacid US20130079373, pp. 15 2-(4-(((N-(tert- INT-11c Synthesized asbutoxycarbonyl)sulfamoyl)amino)- described in methyl)phenyl)propanoicacid US20130079377, pp. 39 2-(3-fluoro-4-(hydroxymethyl)phe- INT-11dSynthesis see below nyl)propanoic acid 2-(4-(3-hydroxyoxetan-3-yl)phe-INT-11e Synthesis see below nyl)propanoic acid 2-(5-fluoro-6-(2-(meth-INT-11f Synthesis see below ylsulfonyl)ethyl)pyridin-3- yl)propanoicacid 2-(6-((2-methoxyethyl)ami- INT-11g Synthesized as no)pyridin-3-described in yl)propanoic acid WO2013013817, pp. 1152-(5-fluoro-6-(hydroxymeth- INT-11h Synthesis see below yl)pyridin-3-yl)propanoic acid 2-(4-(((N-(tert- INT-11i Synthesis see belowbutoxycarbonyl)sulfamoyl)ami- no)methyl)-3- fluorophenyl)propanoic acid

Synthesis of 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid(INT-11a) Synthesis of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate

To a stirred solution of KO^(t)Bu (1.5 g, 7 mmol, 2 eq) in DMF (10 mL)was added a solution of 1-fluoro-2-nitrobenzene (1.0 g, 7.00 mmol, 1 eq)and ethyl 2-chloropropanoate (0.952 g, 7.00 mmol, 1 eq) dropwise at 0°C. The mixture was stirred for 30 min at 0° C. The RM was quenched with1N HCl and extracted with Et₂O, dried (MgSO₄), and concentrated. Thecrude was purified by silica gel column chromatography (100-200 Mesh)using EtOAc/PE (1:19) to get ethyl 2-(3-fluoro-4-nitrophenyl)propanoate(800 mg, 47%) system: EtOAc/PE (1:9), R_(f): 0.25

Synthesis of ethyl 2-(4-amino-3-fluorophenyl)propanoate

To a stirred solution of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate(0.80 g, 3.3 mmol, 1.0 eq) in MeOH (20 mL) was added 10% Pd—C(0.2 g) andstirred under hydrogen atmosphere at RT for 1 h. The RM was filteredthrough celite pad and filtrate was concentrated under reduced pressureto get ethyl 2-(4-amino-3-fluorophenyl)propanoate (0.62 g, 88%) as apale brown liquid. TLC system: EtOAc/PE (2:8), R_(f): 0.2

Synthesis of ethyl 2-(3-fluoro-4-iodophenyl)propanoate

To a stirred solution of ethyl 2-(4-amino-3-fluorophenyl)propanoate(0.12 g, 0.56 mmol, 1.0 eq) and in conc.HCl (3 mL) was added NaNO₂(0.078 g, 1.1 mmol, 2 eq) in water (5 mL) and stirred at −5° C. for 30min. Then KI (0.466 g, 2.80 mmol, 5 eq), I₂ (0.576 g, 2.20 mmol, 4 eq)in water (5 mL) was added and stirred at same temperature for another 30min. The RM was diluted with EtOAc, and washed with NaOCl solution,dried over Na₂SO₄ and concentrated to get ethyl2-(3-fluoro-4-iodophenyl)propanoate (0.3 g, 43%). TLC system: EtOAc/PE(1:9), R_(f): 0.5.

Synthesis of ethyl 2-(3-fluoro-4-vinylphenyl)propanoate

LiCl (490 mg, 11.6 mmol, 1.5 eq), Pd (PPh₃)₄ (444 mg, 0.38 mmol, 0.05eq), were suspended in DMF (10 mL) and argon gas was purged into thesolution for 15 min. The tributylvinyltin (3.6 g, 11.6 mmol, and 1.5 eq)and ethyl 2-(3-fluoro-4-iodophenyl)propanoate were added and heated to55° C. for 16 h. The RM was filtered through a pad of celite and washedwith EtOAc. The organic layer was washed with water, dried andconcentrated. The crude was purified by column chromatography using 10%EtOAc in PE as an eluent to get ethyl2-(3-fluoro-4-vinylphenyl)propanoate (1.1 g, 64%). TLC system: EtOAc/PE(1:9), R_(f): 0.5

Synthesis of ethyl 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate

To a stirred solution of ethyl 2-(3-fluoro-4-vinylphenyl)propanoate (150mg, 0.9 mmol, 1.0 eq) in THF (2.5 mL) was added BH₃.DMS (0.18 mL, 1.6mmol, 1.78 eq) at 0° C. and stirred at RT for 1 h. The RM was cooled to0° C. the 1N NaOH (3 mL) and 30% H₂O₂(2 mL) added and stirred for 30 minand at RT for another 30 min and extracted with EtOAc, dried over Na₂SO₄and concentrated to get ethyl2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate (240 mg crude). Thiscrude was purified by column chromatography using 100-200 silica gel and20% EtOAc in PE as an eluent to get ethyl2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate (100 mg, 46%) as acolourless liquid. TLC system: EtOAc/PE (2:8), R_(f): 0.25

Synthesis of 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid(INT-11a)

To a stirred solution of ethyl2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoate (0.4 g, 1.6 mmol, 1.0eq) in MeOH and H₂O (6 mL, 1:1) was added LiOH.H₂O (349 mg, 8.3 mmol,5.0 eq) and stirred at RT for 2 h. The RM was concentrated and acidifiedwith 2N HCl to get 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoic acid(INT-10a, 150 mg, 42%) as a colorless liquid. TLC system: EtOAc/PE(1:1), R_(f): 0.2

Synthesis of 2-(3-fluoro-4-(hydroxymethyl)phenyl)propanoic acid(INT-11d) Synthesis of (4-bromo-2-fluorophenyl)methanol

To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15 g, 79.4 mmol)in MeOH (100 mL) at −5° C. to 0° C. was added NaBH₄ (6.0 g, 9 mmol) inportions and stirred at RT for 1 h until the starting material wascompletely consumed, as evidenced by TLC analysis. The RM was thendiluted with ice cold water (100 mL) and concentrated under reducedpressure. The residue obtained on concentration was extracted with EtOAc(2×200 mL) and separated. The EtOAc layer was washed with brine (50 mL),dried over anhydrous NaSO₄, filtered and concentrated to afford(4-bromo-2-fluorophenyl)methanol (29 g, from 2 batches each of 15 g of4-bromo-2-fluoro benzaldehyde, 95%) as colorless oil. TLC system:EtOAcPE (3:7), R_(f): 0.3

Synthesis of ((4-bromo-2-fluorobenzyl)oxy) (tert-butyl)dimethylsilane

A stirred solution of 4-bromo-2-fluoro benzaldehyde (49 g, 239 mmol, 1eq) in DCM (400 mL) was treated with imidazole (32.5 g, 478 mmol, 2 eq)followed by TBDMS chloride (39.6 g, 263 mmol, 1.1 eq). The resultingsolution was stirred at RT for 1 h, quenched with water (100 mL) and thelayers were separated. The aqueous layer was extracted with DCM (2×100mL). The combined organic layer was washed with brine (100 mL), dried(Na₂SO₄) and concentrated. The residue upon purification by columnchromatography (silica gel 100-200, EtOAc/PE; 10:90) afforded((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (53 g, 70%) as abrown liquid. TLC system: EtOAc/PE (1:9), R_(f): 0.6

Synthesis oftert-butyl((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane

To a stirred solution of((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (1.2 g, 3.7mmol, 1 eq) in 1,4-dioxane (10 mL) was treated with bis-pinacolatodiboron (1.05 g, 4.15 mmol, 1.1 eq) and KOAc (0.74 g, 7.5 mmol, 2 eq) atRT. The RM was purged with Ar for 20 min. Pd(PPh₃)₂Cl₂ (0.26 g, 0.37mmol, 0.1 eq) was then added and the RM was again purged with Ar for anadditional 15 min. The RM was heated to 100° C. for 3 h until completeconsumption of starting material, as evidenced by TLC analysis. The RMwas concentrated and the obtained crude compound was purified by columnchromatography (60-120 mesh) using PE as eluent to affordtert-butyl((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane(1 g, 74%;) as a pale yellow oil. TLC solvent system: EtOAc/PE (1:9),Rf: 0.7

Synthesis of benzyl 2-bromoacrylate

A suspension of 2-bromoacrylic acid (25.0 g, 167 mmol), BnBr (21.8 mL,183 mmol) and K₂CO₃ (46 g, 0.33 mol) in acetonitrile (250 mL) wasstirred at 80° C. for 3 h until complete consumption of startingmaterial, as evidenced by TLC analysis. The RM was filtered andconcentrated. The obtained crude compound was purified by columnchromatography (100-200 mesh silica gel) using EtOAc/PE (5:95) as eluentto afford benzyl 2-bromoacrylate (22 g, 53%) as a yellow liquid. (TLCsolvent system: EtOAc/PE (5:95), Rf: 0.7

Synthesis of benzyl2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)acrylate

A suspension oftert-butyl((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane(500 mg, 1.36 mmol, 1 eq), Cs₂CO₃ (1.3 g, 4.1 mmol, 3 eq) in DMF (5 mL)was deoxygenated by purging Ar for 30 min at RT. Pd(dppf)Cl₂ (55.6 mg,0.068 mmol, 0.04 eq) was added and purging continued. After 10 min,benzyl 2-bromoacrylate (497 mg, 2.05 mmol, 1.5 eq) was added and stirredat 100° C. for 2 h until complete consumption boronate, as evidenced byTLC analysis. The RM was diluted with EtOAc (10 mL), filtered throughcelite and washed with EtOAc (20 mL). The combined filtrate was washedwith water (3×20 mL), brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The obtained crude compound was purified bycolumn chromatography (100-200 mesh silica gel) using 5% EtOAc in PE aseluent to afford benzyl2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)acrylate (200mg, 42%) as a pale brown oil. TLC system: EtOAc/PE (1:9), Rf: 0.65

Synthesis of 2-(3-fluoro-4-(hydroxymethyl)phenyl)propanoic acid(INT-11d)

A suspension of benzyl2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)acrylate (20mg, 0.050 mmol), 10% Pd(OH)₂ (4 mg) and 10% Pd—C(4 mg) in EtOH (1 mL)was hydrogenated (balloon pressure) at RT for 16 h until completeconsumption of starting material, as evidenced by TLC analysis. The RMwas filtered through Celite, washed with MeOH (2×10 mL). The combinedfiltrate was concentrated and the obtained crude compound was purifiedby dissolving in EtOAc (20 mL) and shaken with aq 10% NaHCO₃ solution(15 mL). The EtOAc layer was separated; the aq layer was acidified withaq citric acid solution (pH 5) and extracted with EtOAc (2×20 mL). Thecombined EtOAc layer was washed with water (15 mL), brine (15 mL) driedover anhydrous Na₂SO₄, filtered and concentrated to afford2-(3-fluoro-4-(hydroxymethyl)phenyl)propanoic acid (INT-11d, 6.7 mg,69%; colorless oil). TLC solvent system: EtOAc/PE (6:4), Rf: 0.2

Synthesis of 2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanoic acid (INT-11e)Synthesis of 3-(4-bromophenyl)oxetan-3-ol

To a stirred solution of 1,4-dibromobenzene (5.00 g, 21.4 mmol) in THF(40 mL) at −78° C. was added n-BuLi (8.5 mL, 21.4 mmol, 2.5 M solutionin hexane), stirred for 30 min and added a solution of oxetan-3-one(1.25 mL, 21.4 mmol) in THF (10 mL) over a period of 15 min. Theresultant RM was allowed to warm to RT and stirred for 3 h. The RM wascooled to 0° C., quenched with aq.NH₄Cl solution, diluted with water (30mL) and extracted with EtOAc (2×50 mL), washed with brine (20 mL), driedover Na₂SO₄ and evaporated to get the crude compound. The crude waspurified by silica gel (100-200 mesh) column chromatography usingEtOAc/PE (1:9) as an eluent to get 3-(4-bromophenyl)oxetan-3-ol (3.0 g,60%). TLC system: EtOAc/PE (1:4), R_(f): 0.2

Synthesis of3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol

To a degassed solution of 3-(4-bromophenyl)oxetan-3-ol (0.500 g, 2.20mmol), bis(pinacolato)diboron (0.61 g, 2.41 mmol) in 1,4-dioxane (10 mL)under Ar was added KOAc (0.65 g, 6.60 mmol) followed by PdCl₂(dppf).DCMcomplex (0.09 g, 0.11 mmol) and degassed for 30 min. The resultant RMwas heated at 100° C. for 2 h. The RM was evaporated under reducedpressure and the crude was triturated with EtOAc/PE (3:7), filtered hotthrough a pad of neutral alumina and evaporated to get crude compound.The crude was triturated with pentane, filtered and dried under vacuumto get3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol(0.42 g, 70%). TLC system: EtOAc/hexane (1:1), R_(f): 0.4

Synthesis of benzyl 2-(4-(3-hydroxyoxetan-3-yl)phenyl)acrylate

To a degassed solution of cesium carbonate (0.94 g, 2.9 mmol) in1,4-dioxane (10 mL), water (1 mL) under Ar was added benzyl2-bromoacrylate (0.35 g, 1.5 mmol, synthesis: see above),3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol(0.40 g, 1.5 mmol) followed by Pd(PPh₃)₄(0.085 g, 0.073 mmol), degassedfor 30 min and heated at 100° C. for 4 h. The RM was evaporated underreduced pressure and the crude was diluted with water (10 mL), extractedwith EtOAc (2×20 mL), washed with brine (10 mL), dried over Na₂SO₄ andevaporated the solvent to get crude compound. The crude was purified bysilica gel column chromatography (100-200 mesh) using EtOAc/PE (3:7) aseluent to get benzyl 2-(4-(3-hydroxyoxetan-3-yl)phenyl)acrylate (0.36 g,80%). TLC system: EtOAc/PE (1:1), R_(f): 0.3

Synthesis of 2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanoic acid (INT-11e)

A solution of benzyl 2-(4-(3-hydroxyoxetan-3-yl)phenyl)acrylate (0.35 g,1.1 mmol) in EtOH (5 mL) was hydrogenated under hydrogen balloonatmosphere with 10% Pd/C (70 mg) at RT for 4 h. The RM was filteredthrough celite pad, washed with EtOH and the solvent was evaporatedunder reduced pressure. The residue was dried under vacuum to get crude2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanoic acid (INT-11e, 0.25 g) whichwas used without further purification. TLC system: 100% EtOAc, R_(f):0.05

Synthesis of2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanoic acid(INT-11f) Synthesis of 5-bromo-3-fluoro-2-vinylpyridine

To a degassed solution of 2,5-dibromo-3-fluoropyridine (0.500 g, 1.97mmol), tributyl (vinyl) tin (0.70 mL, 2.4 mmol) in anhydrous DMF (5 mL)under Ar was added LiCl (0.12 g, 2.95 mmol), followed by Pd(PPh₃)₄(0.12g, 0.098 mmol). The mixture was degassed for 30 min and heated at 60° C.for 16 h. The RM was filtered through celite pad, diluted with water (10mL) and extracted with Et₂O (2×20 mL), washed with brine (10 mL), driedover Na₂SO₄ and evaporated to get the crude compound. The crude waspurified by silica gel (100-200 mesh) column chromatography using 2%EtOAc/PE as an eluent to get crude 5-bromo-3-fluoro-2-vinylpyridine(0.30 g) which was used without further purification. TLC system:EtOAc/PE (1:9), R_(f): 0.8

Synthesis of 5-bromo-3-fluoro-2-(2-(methylsulfonyl)ethyl)pyridine

To a stirred solution of 5-bromo-3-fluoro-2-vinylpyridine (0.30 g, 1.5mmol) in EtOH (5 mL) was added sodium methanesulfinate (0.46 g, 4.5mmol) followed by trifluoroacetic acid (0.33 mL, 4.5 mmol) and heated at60° C. for 2 h. The RM was cooled, diluted with water (10 mL) andbasified with 10% NaHCO₃, extracted with DCM (2×25 mL), washed withbrine (10 mL), dried over Na₂SO₄ and evaporated to get crude compound.The crude was triturated with pentane, filtered and dried under vacuumto get 5-bromo-3-fluoro-2-(2-(methylsulfonyl)ethyl)pyridine (130 mg, 23%over 2 steps). TLC system: EtOAc/PE (1:1), R_(f): 0.3

Synthesis of3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a degassed solution of5-bromo-3-fluoro-2-(2-(methylsulfonyl)ethyl)pyridine (0.25 g, 0.89mmol), bis(pinacolato)diboron (0.23 g, 0.89 mmol) in 1,4-dioxane (10 mL)under Ar was added KOAc (0.26 g, 2.7 mmol) followed by PdCl₂(dppf).DCMcomplex (0.075 g, 0.089 mmol). The RM was degassed for 30 min and heatedat 100° C. for 2 h. The RM was concentrated under reduced pressure andthe crude was triturated with EtOAc/PE (3:7), filtered through a pad ofneutral alumina and evaporated. The crude product was triturated withpentane, filtered the solid and dried under vacuum to get3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.15 g, 51%). TLC system: EtOAc/hexane (3:7), R_(f): 0.05

Synthesis of benzyl2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)acrylate

To a degassed solution of cesium carbonate (0.54 g, 1.7 mmol) in1,4-dioxane (5 mL) and water (1 mL) under Ar was added benzyl2-bromoacrylate (0.20 g, 0.83 mmol, synthesis: see above),3-fluoro-2-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.30 g, 0.91 mmol) followed by Pd(PPh₃)₄ (0.050 g, 0.040 mmol),degassed for 30 min and heated at 100° C. for 2 h. The RM was filteredthrough a pad of celite, the solvent was evaporated under reducedpressure and the crude was diluted with water (10 mL), extracted withEtOAc (2×20 mL), washed with brine (10 mL), dried over Na₂SO₄ andevaporated. The crude was purified by silica gel column chromatography(100-200 mesh) using EtOAc/PE (1:1) as eluent to get benzyl2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)acrylate (0.21 g,70%). TLC system: EtOAc/PE (1:1), R_(f): 0.2

Synthesis of2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanoic acid(INT-11f)

A solution of2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)acrylate (0.20 g,0.55 mmol), 10% Pd/C (50 mg) in EtOH (5 mL) was hydrogenated underhydrogen ballon atmosphere at RT for 3 h. The RM was filtered throughcelite pad, washed with EtOH and the solvent was evaporated underreduced pressure and dried under vacuum to get crude2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanoic acid(INT-11f, 0.10 g). The compound was used without further purification.TLC system: MeOH/DCM (1:9), R_(f): 0.05

Synthesis of 2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid(INT-11h) Synthesis of ethyl 2,6-dichloro-5-fluoronicotinate

Thionyl chloride (50.0 mL, 655 mmol) was added to a stirred solution of2,6-dichloro,5-fluoro,3-nicotinic acid (55.0 g, 262 mmol) in EtOH (300mL) at 0° C. The resulting RM was stirred at reflux for 16 h. The RM wascooled to RT. EtOH was evaporated in vacuo; crude compound was dissolvedin sat NaHCO₃ solution (300 mL) and extracted with EtOAc (3×200 mL).Combined organic layers were washed with water, brine (200 mL), dried(Na₂SO₄) and concentrated to give ethyl 2,6-dichloro-5-fluoronicotinate(61 g, 98%) as a light brown oil which was used without furtherpurification. TLC System: EtOAc/PE (1:1), R_(f): 0.6).

Synthesis of diethyl2-(6-chloro-5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate

Diethyl malonate (48.0 mL, 311 mmol) was added drop wise to a suspensionof NaH (60% in mineral oil; 10.3 g, 259 mmol) in DMF (150 mL) at 0° C.,stirred at RT for 1 h. A solution of ethyl2,6-dichloro-5-fluoronicotinate (62.0 g, 259. mmol) in DMF (100 mL) wasadded at 0° C. and the whole stirred at 50° C. for 16 h. The RM wasquenched with sat NH₄Cl (200 mL) solution and extracted with EtOAc(3×300 mL). Combined organic layer was washed successively with water,brine (200 mL), dried (Na₂SO₄) and concentrated to give crude compound,which was purified by silica gel column chromatography eluting 5% EtOAcin PE to give diethyl2-(6-chloro-5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate (90.0 g,96%) as light yellow oil. TLC system: EtOAc/PE (1:9); R_(f): 0.4

Synthesis of diethyl 2-(5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate

10% palladium hydroxide (9.0 g) was added to a degassed solution ofdiethyl 2-(6-chloro-5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate(90.0 g, 249 mmol) and triethyl amine (70.0 mL, 499 mmol) in EtOH (450mL) at RT. The RM was hydrogenated at RT and 20 psi for 2 h. RM wasfiltered through celite bed, washed with excess EtOH, concentrated togive crude compound, which was dissolved in water and extracted withEtOAc (2×100 mL). Combined organic layer was washed with water (100 mL),brine (50 mL), dried (Na₂SO₄) and concentrated to give diethyl2-(5-(ethoxy-carbonyl)-3-fluoropyridin-2-yl)malonate (80.0 g, 98%) aslight yellow oil. TLC system: EtOAc/PE (1:9), R_(f): 0.4)

Synthesis of 5-fluoro-6-methylnicotinic acid hydrochloride

Conc. HCl (400 mL) was added to diethyl2-(5-(ethoxycarbonyl)-3-fluoropyridin-2-yl)malonate (80.0 g, 245 mmol)at 0° C. The resulting RM was stirred at 120° C. for 24 h. The RM wascooled to RT and aqueous layer was evaporated under reduced pressure,azeotropically dried with toluene to give 5-fluoro-6-methylnicotinicacid hydrochloride (45 g, 96%) as light yellow solid. TLC System:MeOH/DCM (1:9), R_(f): 0.5

Synthesis of ethyl 5-fluoro-6-methylnicotinate

Thionyl chloride (53.0 mL, 711 mmoles) was added to a stirred solutionof 5-fluoro-6-methylnicotinic acid hydrochloride (45.0 g, 237 mmol) inEtOH (250 mL) at 0° C. The resulting RM was stirred at reflux for 16 h.The RM was cooled to RT, EtOH was evaporated, crude compound wasdissolved in sat NaHCO₃ solution (200 mL) and extracted with EtOAc(3×200 mL). Combined organic layers were washed with water, brine (200mL), dried (Na₂SO₄) and concentrated to give ethyl5-fluoro-6-methyl-nicotinate (40.0 g, 92%) as a light brown oil whichwas used in next without further purification. TLC System: EtOAc/PE(1:1), R_(f): 0.6

Synthesis of (5-fluoro-6-methylpyridin-3-yl)methanol

NaBH₄ (24.9 g, 655.73 mmoles) was added to a stirred solution of ethyl5-fluoro-6-methylnicotinate (40.0 g, 219 mmol) in EtOH (400 mL) at 0° C.The resulting RM was stirred at RT for 16 h, EtOH was evaporated, crudecompound was dissolved in water (200 mL) and extracted with EtOAc (3×200mL). Combined organic layers were washed with water, brine (200 mL),dried (Na₂SO₄) and concentrated to give(5-fluoro-6-methylpyridin-3-yl)methanol (30 g, 96%) as a light brown oilwhich was used without further purification. TLC System: EtOAc/PE (1:1),R_(f): 0.2

Synthesis of 5-(chloromethyl)-3-fluoro-2-methylpyridine

Thionyl chloride (150 mL) was added to(5-fluoro-6-methylpyridin-3-yl)methanol (30.0 g, 213 mmol) at 0° C. Theresulting RM was stirred at reflux for 6 h. Thionyl chloride wasevaporated in vacuo; the residue was dissolved in sat NaHCO₃ solution(200 mL) and extracted with EtOAc (3×200 mL). Combined organic layerswere washed with brine (200 mL), dried (Na₂SO₄) and concentrated to give5-(chloro-methyl)-3-fluoro-2-methylpyridine (28 g, 82%) as a brown oilwhich was used without further purification. TLC System: EtOAc/PE (1:1),R_(f): 0.5

Synthesis of 2-(5-fluoro-6-methylpyridin-3-yl)acetonitrile

Sodium cyanide (18.0 g, 352 mmoles) was added to a stirred solution of5-(chloromethyl)-3-fluoro-2-methylpyridine (28.0 g, 176 mmol) in mixtureof EtOH/water (200/20 mL) at 0° C. The resulting RM was stirred atreflux for 6 h. The RM was cooled to RT, quenched with ice cold water(300 mL) and extracted with EtOAc (3×500 mL). Combined organic layerswere washed with water, brine (300 mL), dried (Na₂SO₄) and concentratedto give crude 2-(5-fluoro-6-methylpyridin-3-yl)acetonitrile (24.0 g,90%) as a brown oil which was used without further purification. TLCsystem: EtOAc/PE (1:1), R_(f): 0.35

Synthesis of Methyl 2-(5-fluoro-6-methylpyridin-3-yl)acetate

Trimethylsilyl chloride (100 mL, 800 mmol) was added to a stirredsolution of 2-(5-fluoro-6-methylpyridin-3-yl)acetonitrile (24.0 g, 160mmol) in MeOH (300 mL) at 0° C. The resulting RM was stirred at 90° C.for 8 h in a sealed tube. The RM was cooled to RT. MeOH was evaporated;crude compound was dissolved in sat NaHCO₃ solution (200 mL) andextracted with EtOAc (3×200 mL). Combined organic layers were washedwith water, brine (200 mL), dried (Na₂SO₄) and concentrated to getcrude, which was purified by silica gel column chromatography elutingwith 20% EtOAc in PE to get methyl2-(5-fluoro-6-methylpyridin-3-yl)acetate (22.0 g, 75%) as light yellowoil. TLC system: EtOAc/PE (1:1), R_(f): 0.50)

Synthesis of methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate

A solution of methyl 2-(5-fluoro-6-methylpyridin-3-yl)acetate (22.0 g,120 mmol) in THF (200 mL) was added drop wise to a suspension of 60% NaH(4.80 g, 120 mmol) in THF (150 mL) at 0° C., stirred at same temperaturefor 15 min and then a solution of methyl iodide (7.75 mL, 120 mmol) inTHF (100 mL) was added at 0° C. and the RM was stirred at 0° C. for 2 h.The RM was quenched with sat NH₄Cl (100 mL) and extracted with EtOAc(3×200 mL). Combined organic layers were washed with water, brine (200mL), dried (Na₂SO₄) and concentrated to give crude, which was purifiedby silica gel column chromatography eluting 5% EtOAc in PE to givemethyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate (10.0 g, 44%) as alight yellow oil. TLC system: EtOAc/PE (1:1), R_(f): 0.68

Synthesis of methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoate N-oxide

MCPBA (10.4 g, 60.9 mmol) was added to a stirred solution of methyl2-(5-fluoro-6-methylpyridin-3-yl)propanoate (10.0 g, 50.8 mmol) inchloroform (200 mL) at 0° C. The resulting RM was stirred at RT for 4 h.The RM was diluted with chloroform and successively washed with satNaHCO₃ solution (200 mL), water, brine (200 mL), dried (Na₂SO₄) andconcentrated to give methyl 2-(5-fluoro-6-methylpyridin-3-yl)propanoateN-oxide (11.0 g) as a light yellow oil which was used without furtherpurification. TLC system: EtOAc/PE (1:1), R_(f): 0.1

Synthesis of methyl 2-(6-(acetoxymethyl)-5-fluoropyridin-3-yl)propanoate

Acetic anhydride (110 mL) was added to2-(5-fluoro-6-methylpyridin-3-yl)propanoate N-oxide (11.0 g, 51.6 mmol)at 0° C. The resulting RM was stirred at reflux for 4 h, cooled to RTand quenched with ice cold water. Basified with solid NaHCO₃ andextracted with EtOAc (3×200 mL). Combined organic layers were washedwith water, brine (200 mL), dried (Na₂SO₄) and concentrated to getcrude, which was purified by neutral alumina eluting with 5% EtOAc in PEto get methyl 2-(6-(acetoxymethyl)-5-fluoropyridin-3-yl)propanoate (5.5g, 42% over 2 steps) as a light yellow oil. TLC system: EtOAc/PE (1:1),R_(f): 0.58

Synthesis of 2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid(INT-11h)

Conc. HCl (60.0 mL) was added to2-(6-(acetoxymethyl)-5-fluoropyridin-3-yl)propanoate (5.5 g, 21.6 mmol)at 0° C. The resulting RM was stirred at RT for 5 h. The water wasevaporated under reduced pressure. Resulting crude was redissolved inconc. HCl (60 mL) and stirred at RT for 10 h. The solvent was evaporatedunder reduced pressure and azeotropically dried with toluene to give2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid (INT-11h, 3.5g, 83%) as an off white sticky solid which was used without furtherpurification. TLC System: (MeOH/DCM (15:85), R_(f): 0.33

Synthesis of2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)propanoicacid (INT-11i) Synthesis of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate

To a stirred solution of KOtBu (16.0 g, 142 mmol, 2 eq) in DMF (100 mL)were added a mixture of 1-fluoro-2-nitrobenzene (10.0 g, 70.9 mmol, 1.0eq) and ethyl 2-chloropropanoate (9.0 mL, 70.9 mmol, 1.0 eq) at −50° C.and stirred for 10 min at 0° C. The RM was cooled to −40° C. andquenched with 2N HCl, diluted with water (100 mL), extracted into EtOAc(2×200 mL), dried over Na₂SO₄ and evaporated under reduced pressure. Thecrude was purified by silica gel (60-120 mesh) column chromatographyusing 2-5% EtOAc in PE as eluent to get ethyl2-(3-fluoro-4-nitrophenyl)propanoate (10 g, 58%) as a yellow liquid. TLCsystem: 10% EtOAc in PE, R_(f): 0.4

Synthesis of ethyl 2-(4-amino-3-fluorophenyl)propanoate

To a stirred solution of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate(9.00 g, 37.3 mmol, 1.0 eq) in MeOH (70 mL) was added 10% Pd—C(4.0 g)and the RM was stirred for 1 h at RT under hydrogen atmosphere (50 psi).The RM filtered through celite bed and evaporated to get ethyl2-(4-amino-3-fluorophenyl)propanoate (7.0 g, 88%) as a light brownliquid which was used without further purification. TLC system: 10%EtOAc in PE, R_(f): 0.1

Synthesis of ethyl 2-(3-fluoro-4-iodophenyl)propanoate

To a stirred solution of p-TsOH (20.2 g, 106 mmol, 3 eq) in ACN (100 mL)was added ethyl 2-(4-amino-3-fluorophenyl)propanoate (7.50 g, 35.5 mmol,1.0 eq) at 0° C., stirred for 10 min and added a mixture of KI (14.8 g,88.9 mmol, 2.5 eq.), NaNO₂ (4.90 g, 71.1 mmol, 2 eq) in water (20 mL).The RM was stirred for 2 h at RT, diluted with water (200 mL),neutralized with sat. NaHCO₃ and extracted with EtOAc (2×30 mL). Theorganic layer was washed with brine (20 mL), dried over Na₂SO₄ andevaporated under reduced pressure. The crude compound was purified bysilica gel (60-120 mesh) column chromatography using 2-3% EtOAc in PE aseluent to get ethyl 2-(3-fluoro-4-iodophenyl)propanoate (6.5 g, 65%) asa pale yellow liquid. TLC system: 10% EtOAc in PE R_(f): 0.6

Synthesis of ethyl 2-(4-cyano-3-fluorophenyl)propanoate

To a stirred solution of ethyl 2-(3-fluoro-4-iodophenyl)propanoate (6.8g, 21.1 mmol, 1.0 eq) in NMP (50 mL) was added CuCN (1.84 g, 21.1 mmol,1.0 eq) and stirred for 3 h at 180° C. The RM was diluted with water(100 mL) and extracted into EtOAc (2×50 mL). The organic layer waswashed with brine (30 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The crude was purified by silica gel (60-120) columnchromatography using 5-10% EtOAc in PE as eluent to get ethyl2-(4-cyano-3-fluorophenyl)propanoate (4.5 g, 90%) as a black colourliquid. TLC system: 10% EtOAc in PE, R_(f): 0.4

Synthesis of ethyl 2-(4-(aminomethyl)-3-fluorophenyl)propanoate

To a stirred solution of ethyl 2-(4-cyano-3-fluorophenyl)propanoate(4.50 g, 20.4 mmol, 1.0 eq) in EtOH (40 mL) were added Raney-Ni (2.0 g)followed by aq. NH₃ (2 mL) and the mixture was stirred for 2 h at RTunder hydrogen atmosphere (50 psi). The RM was filtered through celitepad and the filtrate was evaporated under reduced pressure. The crudeproduct was co-distilled twice with toluene to get ethyl2-(4-(aminomethyl)-3-fluorophenyl)propanoate (3.0 g, 75%) as a palegreen liquid. TLC system: EtOAc/PE (1:5), R_(f): 0.05

Synthesis of ethyl2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)propanoate

To a stirred solution of t-BuOH (4.27 mL, 44.4 mmol, 2.5 eq) in DCM (10mL) at RT was added Sulfuryl chloride isocyanate (3.13 mL, 35.4 mmol,2.0 eq) and stirred at RT for 1 h. This RM was added to a solution ofethyl 2-(4-(aminomethyl)-3-fluorophenyl)propanoate (4.00 g, 17.7 mmol,1.0 eq), TEA (7.4 mL, 53 mmol, 3.0 eq) in DCM at 50° C. and refluxed for2 h. The RM was diluted with water (50 mL), extracted with DCM (2×50mL), dried over Na₂SO₄ and evaporated to get crude ethyl2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)propanoate(2.0 g) as an off white solid which was used without furtherpurification. TLC system: EtOAc/PE (1:1), R_(f): 0.6

Synthesis of2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)propanoicacid (INT-11i)

To a stirred solution of ethyl2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)propanoate(4.0 g, 9.9 mmol, 1.0 eq) in MeOH (20 mL) and H₂O (20 mL) was addedLiOH.H₂O (2.0 g, 50 mmol, 5.0 eq) and the mixture was stirred for 16 hat RT. The RM was evaporated, acidified with 10% citric acid solution(˜pH 5), extracted with EtOAc (2×50 mL). The organic layer was driedover Na₂SO₄ and evaporated under reduced pressure. The crude was washedwith n-pentane to get2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)-3-fluorophenyl)propanoicacid (INT-11i, 1.5 g, 39%) as white solid. TLC system: EtOAc/PE (1:1),R_(f): 0.25

Synthesis of azole amides Synthesis ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanamide(EX-1)

To a stirred solution of 2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanoicacid (INT-11a, 100 mg, 0.36 mmol, 1.0 eq) in DCM at 0° C. were added EDCHCl (107 mg, 0.56 mmol, 1.2 eq), HOBT (76 mg, 0.56 mmol, 1.2 eq), TEA(0.203 mL, 1.4 mmol, 3.0 eq) and(4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methanaminehydrochloride (INT-10b-ii, 154 mg, 0.47 mmol, 1.0 eq) and stirred at RTfor 12 h. The RM was diluted with water (10 mL) and extracted with DCM(10 mL), dried (Na₂SO₄) and evaporated. The resulting crude was purifiedby silica gel column chromatography (100-200) using EtOAc/PE (3:7) togetN-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanamide(EX-1, 72 mg, 33%) as a pale yellow solid. TLC system: EtOAc/PE (1:1),R_(f): 0.65; ESI (m/z, MH⁺): 487.0

According to the procedure described for EX-1, the following amides wereprepared:

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3-fluoro-4-(2-hydroxyethyl)phenyl)propanamide(EX-2) from INT-10b-i and INT-11a. TLC system: EtOAc/PE (1:1), R_(f):0.65; ESI (m/z, MH⁺): 471.0

N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide(EX-3) from INT-10a-ii and INT-11b.

N-((2-(tert-butyl)-4-(3-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)-phenyl)propanamide(EX-4) from INT-10a-iii and INT-11b. ESI (m/z, MH⁺): 518.1

N-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(hydroxymethyl)phenyl)propanamide(EX-7) from INT-10a-ii and INT-11d.

N-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-(hydroxymethyl)phenyl)propanamide(EX-8) from INT-10a-iii and INT-11d. ESI (m/z, MH⁺): 441.3

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanamide(EX-9) from INT-10b-i and INT-11e. TLC system: EtOAc/PE (1:1), R_(f):0.2; ESI (m/z, MH⁺): 479.1

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-(3-hydroxyoxetan-3-yl)phenyl)propanamide(EX-10) from INT-10b-ii and INT-11e. TLC system: EtOAc/PE (1:1), R_(f);ESI (m/z, MH⁺): 497.0

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide(EX-11) from INT-10b-i and INT-11f. TLC system: EtOAc, R_(f): 0.4; ESI(m/z, MH⁺): 534.1

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-fluoro-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)propanamide(EX-12) from INT-10b-ii and INT-11f. TLC system: EtOAc, R_(f): 0.4; ESI(m/z, MH⁺): 550.1

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanamide(EX-19) from INT-10b-i and INT-11h. TLC system: EtOAc/PE (1:1), R_(f):0.25; ESI (m/z, MH⁺): 458.2

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanamide(EX-20) from INT-10b-ii and INT-11h. TLC system: EtOAc, R_(f): 0.2; ESI(m/z, MH⁺): 474.1

Synthesis ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-((sulfamoylamino)methyl)phenyl)propanamide(EX-5) Synthesis of tert-butylN-(4-(1-(((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)amino)-1-oxopropan-2-yl)benzyl)sulfamoylcarbamate

To a stirred solution of2-(4-(((N-(tert-butoxycarbonyl)sulfamoyl)amino)methyl)phenyl)propanoicacid (INT-11c, 200 mg, 0.550 mmol, 1.0 eq) in DCM (10 mL) under inertatmosphere was added EDC-HCl (126 mg, 0.660 mmol, 1.2 eq) followed byHOBT (89 mg, 0.66 mmol, 1.2 eq), TEA (0.23 mL, 1.7 mmol, 3.0 eq) at RTand stirred for 15 min, then added(4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methanaminehydrochloride (INT-10b-i, 174 mg, 0.550 mmol, 1.0 eq) and stirred at RTfor 12 h. The RM was diluted with water (50 mL) and extracted into DCM(100 mL), dried over Na₂SO₄ and evaporated under reduced pressure to gettert-butylN-(4-(1-(((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)amino)-1-oxopropan-2-yl)benzyl)sulfamoylcarbamate(300 mg, 87%) as a pale yellow solid. TLC system: EtOAc/PE (1:1), R_(f):0.6

Synthesis ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-((sulfamoylamino)methyl)phenyl)propanamide(EX-5)

To a stirred solution of tert-butylN-(4-(1-(((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)amino)-1-oxopropan-2-yl)benzyl)sulfamoylcarbamate(300 mg, 0.480 mmol, 1.0 eq) in DCM (10 mL) was slowly added TFA (4.0mL) at 0° C. and the RM was stirred for 3 h at RT. The RM was dilutedwith water (30 mL) and basified (pH 8) with sat. NaHCO₃ solution andextracted into DCM (50 mL), washed with brine, dried over Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crude waswashed with Et₂O to getN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(4-((sulfamoylamino)methyl)phenyl)propanamide(EX-5, 125 mg, 49%) as a white solid. TLC system: EtOAc/PE (1:1), R_(f):0.4; ESI (m/z; MH⁺): 515.1

According to the procedure described for EX-5, the following amides wereprepared:

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(4-((sulfamoylamino)methyl)phenyl)propanamide(EX-6) from INT-10b-ii and INT-11c. TLC system: EtOAc/PE (1:1), R_(f):0.4; ESI (m/z, MH⁺): 533.1

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(3-fluoro-4-((sulfamoylamino)methyl)phenyl)propanamide(EX-23) from INT-10b-i and INT-11ii. TLC system: EtOAc/PE (1:1), R_(f):0.25; ESI (m/z, MH⁺): 535.4

N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(3-fluoro-4-((sulfamoylamino)methyl)phenyl)propanamide(EX-24) from INT-10b-ii and INT-11i. TLC system: EtOAc/PE (1:1), R_(f):0.05; ESI (m/z, MH⁺): 551.3

Synthesis ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-hydroxyethyl)amino)pyridin-3-yl)propanamide(EX-13) Synthesis ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-methoxyethyl)amino)pyridin-3-yl)propanamide

To a stirred solution of2-(6-((2-methoxyethyl)amino)pyridin-3-yl)propanoic acid (INT-11g, 200mg, 0.890 mmol, 1.0 eq) in DCM at 0° C. were added EDC.HCl (203 mg, 1.06mmol, 1.2 eq), HOBt (144 mg, 1.06 mmol, 1.2 eq), TEA (0.38 mL, 2.67mmol, 3.0 eq) and(4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methanaminehydrochloride (INT-10b-i, 278 mg, 0.89 mmol, 1.0 eq) and the RM wasstirred at RT for 16 h. The RM was diluted with water (10 mL) andextracted with DCM (10 mL), dried (Na₂SO₄) and concentrated. Theresulting crude was purified by silica gel column chromatography (60-120mesh) using EtOAc/PE(1:1) as eluent to getN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-methoxyethyl)amino)pyridin-3-yl)propanamide(200 mg, 46%) as a pale yellow solid. TLC system: EtOAc (100%), R_(f):0.5

Synthesis ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-hydroxyethyl)amino)pyridin-3-yl)propanamide(EX-13)

To a stirred solution ofN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-methoxyethyl)amino)pyridin-3-yl)propanamide(150 mg, 0.310 mmol, 1.0 eq) in isopropanethiol (5 mL) was addedBF₃.Et₂O (5 mL) at RT and the RM was refluxed for 12 h. The RM wasquenched with aq. NaHCO₃ solution and extracted with DCM (15 mL), driedover Na₂SO₄ and evaporated. The crude was purified by preparative TLCusing EtOAc as eluent and was further washed with Et₂O/pentane (1:9)(2×10 mL) to getN-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-2-(6-((2-hydroxyethyl)amino)pyridin-3-yl)propanamide(EX-13, 110 mg, 75%) as a colorless solid. TLC system: EtOAc, R_(f):0.15; ESI (m/z; MH⁺): 469.4

According to the procedure described for EX-13,N-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-2-(6-((2-hydroxyethyl)amino)pyridin-3-yl)propanamide(EX-14) was prepared from INT-10b-ii and INT-11g. TLC system: EtOAc/PE(9:1), R_(f): 0.2; ESI (m/z, MH⁺): 485.1

Chiral Separation of Amides

Racemic EX-14 was subjected to chiral preparative SFC. Column:Chiralpak-ASH (250×30 mm); eluent CO₂/MeOH 3/1; flow 70 g/min; pressure100 bar; loading per injection: 35 mg.

First eluting enantiomer (EX-15): ESI (m/z, MH⁺): 485.2

Second eluting enantiomer: (EX-16): ESI (m/z, MH⁺): 485.3

Racemic EX-13 was subjected to chiral preparative HPLC. Column:Chiralpak-IB (250×20 mm); eluent hexane/DCM/EtOH/diethylamine80/10/10/0.1; flow 22 mL/min; loading per injection: 5 mg.

First eluting enantiomer (EX-17): ESI (m/z, MH⁺): 468.8

Second eluting enantiomer: (EX-18): ESI (m/z, MH⁺): 468.9

Racemic EX-19 was subjected to chiral preparative HPLC. Column:Chiralpak-AY-H (250×30 mm); eluenthexane/isopropanol/EtOH/trifluoroacetic acid 80/20/2/0.1; flow 30mL/min; loading per injection: 30 mg.

First eluting enantiomer (EX-21): ESI (m/z, MH⁺): 457.9

Second eluting enantiomer: (EX-22): ESI (m/z, MH⁺): 457.8

Azole ureas can be synthesized from azole methylamines hydrochloridesINT-10 and the carbamates INT-14. These carbamates can be prepared byreacting the amines INT-12 with phenylchloroformate 13 (Scheme 3)

Synthesis of Phenyl Carbamates INT-14

Table 3 summarizes the phenyl carbamates INT-14 which syntheses hasalready been described in literature.

TABLE 3 Literature described phenyl carbamates INT-14. phenyl(6-(((tert- INT-14a WO2013013815,butyldimethylsilyl)oxy)methyl)pyridin-3- pp. 230 yl)carbamate phenyl(6-(2-((tert- INT-14b WO2013013815,butyldimethylsilyl)oxy)ethyl)pyridin-3- pp. 141 yl)carbamate phenyl (4-INT-14c WO2013068462, (methylsulfonamidometh- pp. 72 yl)phenyl)carbamatetert-butyl INT-14e WO2013068462, N-(4-(phenyloxycarbonylamino)- pp. 78benzyl)sulfamoylcarbamate phenyl (3-fluoro-4- INT-14n WO2013068462,(methylsulfonamidometh- pp. 76 yl)phenyl)carbamate phenyl (3-fluoro-4-INT-14o WO2013068467, (hydroxymethyl)phenyl)carbamate pp. 65

Synthesis of phenyl (6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate(INT-14f) Synthesis of 5-bromopicolinaldehyde

To a stirred solution of 5-bromopicolinonitrile (5.00 g, 27.3 mmol, 1eq) in THF (50 mL) was added 1M DIBAL (41 mL, 40.98 mmol, 1 eq) slowlydropwise at −78° C. and the RM was stirred for 6 h at same temperature.The RM was quenched with 1N HCl at −78° C. and neutralized withsaturated NaHCO₃ solution, extracted with EtOAc, dried (Na₂SO₄), andconcentrated to get 5-bromopicolinaldehyde (3.00 g, 59%), which was usedwithout further purification. TLC system: EtOAc/PE (2:3), R_(f): 0.5

Synthesis of (5-bromopyridin-2-yl)methanol

To a stirred solution of 5-bromopicolinaldehyde (3.0 g, 16 mmol, 1.0 eq)in MeOH (30 mL) at 0° C. was added NaBH₄ (1.16 g, 32.0 mmol, 2.0 eq) andthe RM was stirred for 1 h at 0° C., warmed to RT and stirred for 1 h.The RM was concentrated, diluted with water and extracted with EtOAc,dried (Na₂SO₄) and evaporated to get (5-bromopyridin-2-yl)methanol (1.5g, 49%), which was used without further purification. TLC system:EtOAc/PE (2:3), R_(f): 0.55

Synthesis of 5-bromo-2-((2-methoxyethoxy)methyl)pyridine

To a stirred solution of (5-bromopyridin-2-yl)methanol (0.100 g, 0.531mmol, 1.0 eq) in THF (10 mL) was added NaH (38 mg, 1.5 mmol, 3.0 eq) at0° C. and stirred for 10 min, then 1-bromo-2-methoxyethane (0.1 mL, 1.0mmol, 2.0 eq) was added and the RM was stirred at RT for 16 h. The RMwas quenched with ice cold water, extracted with EtOAc, dried (Na₂SO₄)and evaporated to get 5-bromo-2-((2-methoxyethoxy)methyl)pyridine (0.1g, crude). TLC system: EtOAc/PE (1:9), R_(f): 0.5

Synthesis ofN-(diphenylmethylene)-6-((2-methoxyethoxy)methyl)pyridin-3-amine

To a stirred solution of 5-bromo-2-((2-methoxyethoxy)methyl)pyridine(0.15 g, 0.61 mmol, 1.0 eq) in toluene (5 mL) were addedbenzophenoneimine (0.12 mL, 0.73 mmol, 1.2 eq), Pd₂dba₃ (56 mg, 0.061mmol, 0.1 eq) Cs₂CO₃ (0.3 g, 0.92 mmol, 1.5 eq), under N₂. The RM wasrefluxed for 16 h, diluted with water (5 mL) and extracted with EtOAc(10 mL), dried over Na₂SO₄ and evaporated to getN-(diphenyl-methylene)-6-((2-methoxyethoxy)methyl)pyridin-3-amine (200mg, crude). The crude was used directly for next step without furtherpurification.

Synthesis of 6-((2-methoxyethoxy)methyl)pyridin-3-amine

To a solution ofN-(diphenylmethylene)-6-((2-methoxyethoxy)methyl)pyridin-3-amine (200mg) in MeOH was added conc HCl (2 mL) and the RM was stirred at RT for30 min. The RM was diluted with water (5 mL), neutralized with TEA andextracted with EtOAc (10 mL) and evaporated under reduced pressure. Thecrude obtained was washed with Et₂O (10 mL) to get6-((2-methoxyethoxy)methyl)pyridin-3-amine (100 mg), which was usedwithout further purification. TLC system: MeOH/DCM (1:19), R_(f): 0.2

Synthesis of phenyl (6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate(INT-14f)

To a stirred solution of 6-((2-methoxyethoxy)methyl)pyridin-3-amine (450mg, 2.48 mmol, 1.0 eq) in acetone (5 mL) were added phenyl chloroformate(13, 0.313 mL, 2.48 mmol, 1.0 eq), and pyridine (0.6 mL, 7.5 mmol, 3.0eq) at 0° C. The RM was stirred at same temperature for 2 h. The RM wasconcentrated under reduced pressure, the residue was diluted with DCM(20 mL and washed with water (8 mL). The aqueous phase was extractedwith DCM, the combined organic phases were dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified by silicagel (100-200 mesh) column chromatography using EtOAc/PE (4:1) as eluentto get to get phenyl (6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate(INT-14f, 400 mg, 53%) as a colorless solid. TLC system MeOH/DCM (1:19),R_(f): 0.4

Synthesis of phenyl(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)carbamate(INT-14d) Synthesis of 2-((5-nitropyridin-2-yl)oxy)ethanol

To a stirred solution of 60% NaH in mineral oil (302 mg, 12.6 mmol, 2.0eq) in THF (10 mL) was added ethylene glycol (783 mg, 12.6 mmol, 2.0eq.) at 0° C. and stirred for 15 min. 2-chloro-5-nitropyridine (1.00 g,6.31 mmol, 1.0 eq.) in DMF (3 mL) was added, the RM was allowed to warmto RT and heated to 50° C. for 3 h. The RM was cooled and quenched withice cold water (10 mL), extracted with EtOAc (2×15 mL), washed withbrine, dried over anhydrous Na₂SO₄, evaporated and dried under vacuum toget crude. The crude was purified by silica gel column chromatography(100-200 mesh) using EtOAc/PE (1:4) as eluent to get2-((5-nitropyridin-2-yl)oxy)ethanol (900 mg, 77%) as a colourlessliquid. TLC system: EtOAc/PE (7:3), R_(f): 0.5

Synthesis of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine

To a stirred solution of 2-((5-nitropyridin-2-yl)oxy)ethanol (900 mg,4.89 mmol, 1.0 eq.) in DCM (10 mL) was added imidazole (665 mg, 9.78mmol, 2 eq.), the RM was cooled to 0° C. and TBDMSCl (820 mg, 5.40 mmol,1.1 eq.) was added. The RM was stirred for 2 h at RT, diluted with water(20 mL), extracted with DCM (2×25 mL), washed with brine (10 mL), driedover anhydrous Na₂SO₄ and evaporated to get2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine (1.26 g, 87%)which was used without further purification. TLC system: EtOAc/PE (1:1),R_(f): 0.5.

Synthesis of 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-amine

To a stirred solution of2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine (1.25 g, 4.36mmol, 1.0 eq.) in MeOH (20 mL) was added 10% Pd/C (200 mg) and themixture was hydrogenated using H₂ balloon at RT for 2 h. The RM wasfiltered through celite bed and concentrated under reduced pressure toget crude. The crude was purified by preparative HPLC to get6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-pyridin-3-amine (820 mg, 72%)as a brown solid. TLC system: EtOAC/PE (9:1), R_(f): 0.2

Synthesis of phenyl(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)carbamate(INT-14d)

To a stirred solution of6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-amine (150 mg, 0.600mmol, 1.0 eq.) in acetone (5 mL) were added PhOCOCl (0.078 mL, 0.67mmol, 1.1 eq.) and pyridine (0.14 mL, 1.8 mmol, 3 eq.) at 0° C. The RMwas stirred at same temperature for 1 h. The solvent was evaporated andthe residue was diluted with DCM (10 mL), washed with water (10 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crude waswashed with Et₂O (5 mL) to get phenyl(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)carbamate(INT-14d, 125 mg, 56%) as a white solid. TLC system: EtOAC/PE (3:7),R_(f): 0.6.

Synthesis of phenyl(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-yl)carbamate(INT-14ac) Synthesis of 1-(5-nitropyridin-2-yl)azetidin-3-ol

A mixture of 2-chloro-5-nitropyridine (1.00 g, 6.32 mmol), azetidin-3-olhydrochloride (1.04 g, 9.50 mmol) and TEA (1.3 mL, 9.5 mmol) in DMF (33mL) was heated at 100° C. for 20 h. The RM was cooled to RT, dilutedwith water (30 mL), extracted with EtOAc (2×30 mL), washed with water(30 mL) and brine (20 mL), dried over Na₂SO₄ and evaporated the solventto get 1-(5-nitropyridin-2-yl)azetidin-3-ol (0.52 g, 42%) which was usedwithout further purification. TLC system: EtOAc/PE (1:9), R_(f): 0.2

Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitropyridine

To a stirred solution of 1-(5-nitropyridin-2-yl)azetidin-3-ol (0.52 g,2.7 mmol) in DCM (10 mL) at 0° C. was added imidazole (0.32 g, 5.3 mmol)followed by TBDMSCl (0.80 g, 5.3 mmol) and stirred at RT for 16 h. TheRM was diluted with water (10 mL), extracted with DCM (2×20 mL), washedwith brine (10 mL), dried over Na₂SO₄ and evaporated to get crudecompound. The crude was purified by silica gel column chromatography(100-200 mesh) using 6% EtOAc/PE as eluent to get2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitropyridine (0.60g, 75%). TLC system: EtOAc/PE (3:7), R_(f): 0.6

Synthesis of6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-amine

A solution of2-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-5-nitropyridine (0.60g, 1.94 mmol), 10% Pd/C (300 mg) in EtOH (20 mL) was hydrogenated underhydrogen balloon at RT for 14 h. The RM was filtered through a celitepad, washed with EtOH and the solvent was evaporated under reducedpressure to get6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-amine (0.41g, 76%). TLC system: EtOAc/PE (3:7), R_(f): 0.6

Synthesis of phenyl(6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-yl)carbamate(INT-14ac)

To a stirred solution6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-3-amine (0.40g, 1.4 mmol) in acetone (10 mL) at 0° C. was added pyridine (0.17 mL,2.1 mmol) followed by phenyl chloroformate (0.22 mL, 1.7 mmol) and theRM was stirred for 2 h. The RM was evaporated under reduced pressure andthe crude residue was diluted with water (10 mL), extracted with EtOAc(2×20 mL), washed with brine (10 mL), dried over Na₂SO₄ and evaporatedto get phenyl(6-(3-((tert-butyldimethylsilyl)oxy)-azetidin-1-yl)pyridin-3-yl)carbamate(INT-14ac, 0.30 g, 52%). TLC system: EtOAc/PE (3:7), R_(f): 0.7

Table 4 summarizes the phenyl carbamates INT-14 which were obtained fromcommercially available amines INT-12 and phenyl chloroformiate (13) asdescribed for INT-14f.

TABLE 4 phenyl carbamates from commercially available amines phenylbenzo[d][1,3]dioxol-5-ylcarbamate INT-14g phenyl(2,3-dihydro-1H-inden-4-yl)carbamate INT-14h phenylisoquinolin-6-ylcarbamate INT-14i phenyl quinolin-5-ylcarbamate INT-14jphenyl (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate INT-14k phenyl(2,3-dihydro-1H-inden-5-yl)carbamate INT-14l phenylisoquinolin-5-ylcarbamate INT-14m phenyl(3-methoxypyridin-4-yl)carbamate INT-14p phenyl pyrimidin-5-ylcarbamateINT-14q phenyl (5-methylpyridin-2-yl)carbamate INT-14r phenylpyridin-4-ylcarbamate INT-14s phenyl pyridin-2-ylcarbamate INT-14tphenyl pyridin-3-ylcarbamate INT-14u phenyl(3-methylpyridin-4-yl)carbamate INT-14v phenyl(2-methylpyridin-4-yl)carbamate INT-14w phenyl(6-fluoropyridin-3-yl)carbamate INT-14x phenyl(6-methylpyridin-3-yl)carbamate INT-14y phenyl(2-methylpyrimidin-5-yl)carbamate INT-14z phenyl(2-methoxypyrimidin-5-yl)carbamate INT-14aa

Phenyl (6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)carbamate (INT-14ab) wassynthesized from 6-(2-(methylsulfonyl)ethyl)pyridin-3-amine (synthesis:see WO20130131815, pp. 129) and phenyl chloroformiate (13) as describedfor INT-14f.

Synthesis of Azole Ureas Synthesis of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea(EX-25) Synthesis of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)urea

To a stirred solution of(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methanamine hydrochloride(INT-10a-i, 200 mg, 0.600 mmol, 1.0 eq) in DCM (5 mL) were added TEA(192 mg, 1.800 mmol, 3 eq) and phenyl(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)carbamate(INT-14a, 245 mg, 0.600 mmol, 1.0 eq) at 0° C. and the mixture wasstirred at RT for 16 h. The RM was diluted with DCM, washed with waterand extracted with DCM. Organic layer was dried over Na₂SO₄,concentrated under reduced pressure to get1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)urea(300 mg, 85%) as a brown liquid. TLC system: EtOAc/PE (1:1), R_(f): 0.4

Synthesis of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea(EX-25)

To a stirred solution of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)urea(300 mg, 0.568 mmol, 1.0 eq) in THF (20 mL) was added 2N HCl (10 mL) at0° C. and the RM was stirred at RT for 4 h. Then the RM wasconcentrated, diluted with EtOAc (20 mL) and washed with water (20 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crude waspurified by silica gel column chromatography (100-200 mesh) usingMeOH/DCM (1:9) as eluent to get1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea(EX-25, 110 mg, 46%) as pale yellow solid. TLC system: MeOH/DCM (1:9),R_(f): 0.2; ESI (m/z, MH⁺): 415.0

According to the procedure described for EX-25, the following ureas wereprepared:

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea(EX-26) from INT-10a-ii and INT-14a. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 431.0

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea(EX-27) from INT-10b-i and INT-14a. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 427.3

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(hydroxymethyl)pyridin-3-yl)urea(EX-28) from INT-10b-ii and INT-14a. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 443.3

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea(EX-32) from INT-10b-i and INT-14ac. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 451.2

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)urea(EX-33) from INT-10b-ii and INT-14ac. TLC system: MeOH/DCM (1:9), R_(f):0.1; ESI (m/z, MH⁺): 484.2

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea(EX-34) from INT-10b-ii and INT-14b. TLC system: EtOAc, R_(f): 0.2; ESI(m/z, MH⁺): 457.3

1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea(EX-35) from INT-10a-i and INT-14b. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 429.0

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea(EX-36) from INT-10a-ii and INT-14b. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 445.0

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-hydroxyethyl)pyridin-3-yl)urea(EX-37) from INT-10b-i and INT-14b. TLC system: EtOAc, R_(f): 0.2; ESI(m/z, MH⁺): 441.3

1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy)pyridin-3-yl)urea(EX-40) from INT-10a-i and INT-14d. TLC system: EtOAc/PE (1:1), R_(f):0.4; ESI (m/z, MH⁺): 445.0

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy)pyridin-3-yl)urea(EX-41) from INT-10a-ii and INT-14d. TLC system: EtOAc/PE (1:1), R_(f):0.4; ESI (m/z, MH⁺): 460.8

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy)pyridin-3-yl)urea(EX-42) from INT-10b-i and INT-14d. TLC system: EtOAc/PE (1:1), R_(f):0.a; ESI (m/z, MH⁺): 457.3

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-hydroxyethoxy)pyridin-3-yl)urea(EX-43) from INT-10b-ii and INT-14d. TLC system: MeOH/DCM (1:9), R_(f):0.2; ESI (m/z, MH⁺): 473.1

Synthesis ofN-((5-(3-chlorophenyl)-2-(tertbutyl)oxazol-4-yl)methyl)-N′-(4-((sulfamoyl-amino)methyl)phenyl)urea(EX-44) Synthesis of tert-butylN-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benzyl)sulfamoylcarbamate

To a stirred solution of(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methanamine hydrochloride(INT-10a-i, 160 mg, 0.530 mmol, 1.0 eq) in DCM (20 mL) was added TEA(0.38 mL, 2.7 mmol, 5.0 eq) and stirred at RT for 10 min. Thentert-butyl N-(4-(phenyloxycarbonylamino)-benzyl)sulfamoylcarbamate(INT-14e, 224 mg, 0.53 mmol, 1.0 eq) was added and the mixture wasstirred at RT for 16 h. The RM was diluted with DCM (10 mL) and washedwith water, dried and evaporated to get crude tert-butylN-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benzyl)-sulfamoylcarbamate(300 mg) as thick brown liquid which was used without furtherpurification. TLC system: EtOAc/PE (1:1), R_(f): 0.4.

Synthesis ofN-((5-(3-chlorophenyl)-2-(tertbutyl)oxazol-5-yl)methyl)-N′-(4-((sulfamoylamino)methyl)phenyl)urea(EX-44)

To a stirred solution ofN-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benzyl)sulfamoylcarbamate(0.30 g, 0.50 mmol, 1.0 eq) in DCM (10 mL) was added TFA (2 mL) at 0°C., stirred for 30 min and then at RT for another 2 h. The RM was slowlyquenched with saturated NaHCO₃ solution (pH 8) and extracted with DCM(20 mL), dried (Na₂SO₄) and evaporated under reduced pressure. Thiscrude was purified by preparative TLC to getN-((5-(3-chlorophenyl)-2-(tert-butyl)oxazol-5-yl)methyl)-N′-(4-((sulfamoylamino)methyl)phenyl)urea(EX-44, 75 mg, 28% over 2 steps) as off-white solid. TLC system: EtOAc,R_(f): 0.25; ESI (m/z MH⁺): 491.8

According to the procedure described for EX-44,N-((5-(3-chlorophenyl)-2-(tertbutyl)thiazol-5-yl)methyl)-N′-(4-((sulfamoylamino)methyl)phenyl)urea(EX-45) from INT-10aii and INT-14e. TLC system: EtOAc/PE (1:1), R_(f):0.15; ESI (m/z, MH⁺): 507.8

Synthesis of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)ureadihydrochloride (EX-46) Synthesis of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-methoxyethoxy)methyl)pyridin-3-yl)urea

To a stirred solution of(2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methanamine hydrochloride(INT-10a-i, 150 mg, 0.500 mmol, 1.0 eq) in DCM (5 mL) were added TEA(151 mg, 1.50 mmol, 3 eq) and phenyl(6-((2-methoxyethoxy)methyl)pyridin-3-yl)carbamate (INT-14f, 151 mg,0.500 mmol, 1.0 eq) at 0° C. and stirred at RT for 12 h. Then the RM wasdiluted with DCM (10 mL), washed with water (20 mL) and dried overNa₂SO₄ and concentrated under reduced pressure to get1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-methoxyethoxy)methyl)pyridin-3-yl)urea(200 mg, 85%) as a yellow liquid which was used without furtherpurification. TLC system: EtOAc/PE (7:3), R_(f): 0.5

Synthesis of1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)urea dihydrochloride (EX-46)

To a stirred solution of get1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-methoxyethoxy)methyl)pyridin-3-yl)urea(200 mg, 0.423 mmol, 1.0 eq) in DCM (20 mL) was added 1 M BBr₃ solutionin DCM (0.85 mL, 0.87 mmol, 2.0 eq), at −78° C. and stirred at RT for 2h. The RM was quenched with saturated NaHCO₃ solution (10 mL), dilutedwith DCM (10 mL), washed with water (20 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified bypreparative HPLC, dissolved in Et₂O (5 mL) and precipitated with HCl inEt₂O to get1-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)ureadihydrochloride (EX-46, 60 mg, 30%) as off white solid. TLC system:EtOAC/PE (9:1), R_(f): 0.4; ESI (m/z MH⁺): 459.2

According to the procedure described for EX-46, the following ureas wereprepared:

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)ureadihydrochloride (EX-47) from INT-10a-ii and INT-14f. TLC system:EtOAc/PE (9:1), R_(f): 0.4; ESI (m/z, MH⁺): 475.4

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)ureadihydrochloride (EX-48) from INT-10b-i and INT-14f. TLC system: EtOAc/PE(9:1), R_(f): 0.4; ESI (m/z, MH⁺): 471.1

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-((2-hydroxyethoxy)methyl)pyridin-3-yl)ureadihydrochloride (EX-49) from INT-10b-ii and INT-14f. TLC system:EtOAc/PE (9:1), R_(f): 0.2; ESI (m/z, MH⁺): 487.2

Synthesis of1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea(EX-30)

To a stirred solution of(4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methanaminehydrochloride (INT-10b-i, 0.15 g, 0.48 mmol) in DCM (10 mL) at 0° C. wasadded TEA (0.21 mL, 1.44 mmol) followed by phenyl(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)carbamate (INT-14ab, 0.15 g,0.48 mmol) and stirred at rt for 16 h. The RM was diluted with water (10mL), extracted with DCM (2×20 mL), washed with brine (10 mL), dried overanhydrous Na₂SO₄ and evaporated the solvent to get the crude compound.The crude was purified by silica gel column chromatography (60-120 mesh)using 5% MeOH in DCM as eluent to get1-((4-(3-chlorophenyl)-2-(trifluoromethyl)oxazol-5-yl)methyl)-3-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea(EX-30, 0.16 g, 66%). TLC system: EtOAc, R_(f): 0.2, ESI (m/z MH⁺):503.3

According to the procedure described for EX-30, the following ureas wereprepared:

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-methoxypyrimidin-5-yl)urea(EX-29) from INT-10a-ii and INT-14a. ESI (m/z, MH⁺): 432.2

1-((4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)methyl)-3-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)urea(EX-31) from INT-10b-ii and INT-14ab. TLC system: EtOAc/hexane (7:3),R_(f): 0.2; ESI (m/z, MH⁺): 518.9

N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)oxazol-5-yl)methyl)ureido)benzyl)methanesulfonamide(EX-38) from INT-10a-i and INT-14c. TLC system: MeOH/DCM (1:9), R_(f):0.4; ESI (m/z, MH⁺): 491.0

N-(4-(3-((2-(tert-butyl)-4-(3-fluorophenyl)thiazol-5-yl)methyl)ureido)benzyl)methanesulfonamide(EX-39) from INT-10a-iv and INT-14c. TLC system: EtOAc/PE (7:3), R_(f):0.4; ESI (m/z, MH⁺): 507.0

1-(benzo[d][1,3]dioxol-5-yl)-3-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)urea(EX-50) from INT-10a-ii and INT-14g.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydro-1H-inden-4-yl)urea(EX-51) from INT-10a-ii and INT-14h.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoquinolin-6-yl)urea(EX-52) from INT-10a-ii and INT-14i.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(quinolin-5-yl)urea(EX-53) from INT-10a-ii and INT-14j.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea(EX-54) from INT-10a-ii and INT-14k.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2,3-dihydro-1H-inden-5-yl)urea(EX-55) from INT-10a-ii and INT-14l. ESI (m/z, MH⁺): 440.2

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(isoquinolin-5-yl)urea(EX-56) from INT-10a-ii and INT-14m. ESI (m/z, MH⁺): 451.2

N-(4-(3-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)ureido)-2-fluorobenzyl)methanesulfonamide(EX-57) from INT-10a-ii and INT-14n.

N-(4-(3-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)ureido)-2-fluorobenzyl)methanesulfonamide(EX-58) from INT-10a-iii and INT-14n.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea(EX-59) from INT-10a-ii and INT-14o. ESI (m/z, MH⁺): 448.1

1-((2-(tert-butyl)-4-(m-tolyl)thiazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea(EX-60) from INT-10a-iii and INT-14o.

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-methoxypyridin-4-yl)urea(EX-61) from INT-10a-ii and INT-14p. ESI (m/z, MH⁺): 431.2

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyrimidin-5-yl)urea(EX-62) from INT-10a-ii and INT-14q. ESI (m/z, MH⁺): 402.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(5-methylpyridin-2-yl)urea(EX-63) from INT-10a-ii and INT-14r. ESI (m/z, MH⁺): 415.2

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-4-yl)urea(EX-64) from INT-10a-ii and INT-14s. ESI (m/z, MH⁺): 401.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-2-yl)urea(EX-65) from INT-10a-ii and INT-14t. ESI (m/z, MH⁺): 401.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(pyridin-3-yl)urea(EX-66) from INT-10a-ii and INT-14u. ESI (m/z, MH⁺): 401.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(3-methylpyridin-4-yl)urea(EX-67) from INT-10a-ii and INT-14v. ESI (m/z, MH⁺): 415.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-methylpyridin-4-yl)urea(EX-68) from INT-10a-ii and INT-14w. ESI (m/z, MH⁺): 415.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-fluoropyridin-3-yl)urea(EX-69) from INT-10a-ii and INT-14x. ESI (m/z, MH⁺): 419.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(6-methylpyridin-3-yl)urea(EX-70) from INT-10a-ii and INT-14y. ESI (m/z, MH⁺): 415.1

1-((2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)methyl)-3-(2-methylpyrimidin-5-yl)urea(EX-71) from INT-10a-ii and INT-14z. ESI (m/z, MH⁺): 416.2

Pharmacological Methods FLIPR Assay:

The FLIPR protocol consists of 2 substance additions during a kineticmeasurement. First the compounds to be tested (5 μM) are pipetted ontothe cells and the Ca²⁺ influx is determined in comparison to the control(capsaicin 10 μM), providing the result as % activation and representingthe compound-alone effect (calculation at peak signal related tobaseline). A Ca²⁺ influx of 10%-60% reveals a partial agonist (pAG), aCa²⁺ influx of >60% relates to a pure agonist (AG). After 5 minincubation, the Ca²⁺ influx is related to an injection of 100 nM ofcapsaicin and thereby the antagonistic effect of the test compoundsdetected.

Desensitising agonists and antagonists lead to suppression of the Ca²⁺influx. The % inhibition is calculated compared to the maximumachievable inhibition with 10 μM of capsaicin. Triple analyses (n=3) arecarried out and repeated in at least 3 independent experiments.

Starting from the percentage displacement caused by differentconcentrations of the compounds to be tested of general formula I, IC₅₀inhibitory concentrations which cause a 50-% displacement of capsaicinwere calculated. K_(i) values for the test substances were obtained byconversion by means of the Cheng-Prusoff equation (Cheng, Prusoff;Biochem. Pharmacol. 22, 3099-3108, 1973).

Method:

Chinese hamster ovary cells (CHO K1 cells, European Collection of CellCultures (ECACC) United Kingdom) are stably transfected with the VR1gene. For functional testing, these cells are plated out onpoly-D-lysine-coated black 96-well plates having a clear base (BDBiosciences, Heidelberg, Germany) at a density of 25,000 cells/well. Thecells are incubated overnight at 37° C. and 5% CO₂ in a culture medium(Ham's F12 nutrient mixture, 10% by volume of FCS (foetal calf serum),18 μg/ml of L-proline). The next day the cells are incubated with Fluo-4(Fluo-4 2 μM, 0.01% by volume of Pluronic F127, Molecular Probes in HBSS(Hank's buffered saline solution), Gibco Invitrogen GmbH, Karlsruhe,Germany) for 30 min at 37° C. Subsequently, the plates are washed threetimes with HBSS buffer and after further incubation for 15 min at RTused for Ca²⁺ measurement in a FLIPR assay. The Ca²⁺-dependentfluorescence is measured before and after the addition of the substancesto be tested (λex wavelength=488 nm, λem=540 nm). Quantification iscarried out by measuring the highest fluorescence intensity (FC,fluorescence counts) over time.

Pharmacological Data

The affinity of the compounds according to the invention for thevanilloid receptor 1 was determined as described hereinbefore(pharmacological method I or II). The compounds according to theinvention display affinity to the VR1/TRPV1 receptor (Table 5).

In Table 5 the abbreviations below have the following meanings:Cap=capsaicin; AG=agonist; pAG=partial agonist; ne=no effect (<10% @ 5μM); nd=not determined; The value after the “@” symbol indicates theconcentration at which the inhibition (as a percentage) was respectivelydetermined.

TABLE 5 (f) Ki Exemplary (human) [nM] Compound Cap EX-01 1.4 EX-02 28.4EX-03 0.6 EX-04 pAG (1.0) EX-05 7.5 EX-06 0.7 EX-07 AG EX-08 AG EX-09 pAG (73.8) EX-10 pAG (8.8) EX-11 53.1 EX-12 1.1 EX-13 5.2 EX-14 0.7EX-15 0.4 EX-16 41.9 EX-17 0.7 EX-18 96.7 EX-19 13.8 EX-20 0.3 EX-21 neEX-22 ne EX-23 4.7 EX-24 2.35 EX-25  pAG (73.1) EX-26  pAG (10.2) EX-2762.5 EX-28 19.4 EX-29 nd EX-30 41%@5 μM EX-31 48.8 EX-32 60.82225 EX-3324.6 EX-34  pAG (30.2) EX-35 78.4 EX-36 AG EX-37 46%@5 μM EX-38 52.6EX-39 17.6 EX-40 43.6 EX-41 27.5 EX-42 103.4 EX-43 29.8 EX-44 29.9 EX-459.1 EX-46 55%@5 μM EX-47 33.3 EX-48 31%@5 μM EX-49 35 EX-50 pAG (5.6)EX-51 pAG (2.9) EX-52 AG EX-53 AG EX-54 5.9 EX-55 12.3 EX-56 0.1 EX-576.6 EX-58 2.3 EX-59 pAG (1.1) EX-60 pAG (3.2) EX-61 nd EX-62 nd EX-63 ndEX-64 nd EX-65 nd EX-66 nd EX-67 nd EX-68 nd EX-69 nd EX-70 nd EX-71 nd

Having now fully described the present invention in some detail by wayof illustration and examples for purposes of clarity of understanding,it will be obvious to one of ordinary skill in the art that the same canbe performed by modifying or changing the invention within a wide andequivalent range of conditions, formulations and other parameterswithout affecting the scope of the invention or any specific embodimentthereof, and that such modifications or changes are intended to beencompassed within the scope of the appended claims.

When a group of materials, compositions, components or compounds isdisclosed herein, it is understood that all individual members of thosegroups and all subgroups thereof are disclosed separately. Everyformulation or combination of components described or exemplified hereincan be used to practice the invention, unless otherwise stated. Whenevera range is given in the specification, for example, a temperature range,a time range, or a composition range, all intermediate ranges andsubranges, as well as all individual values included in the ranges givenare intended to be included in the disclosure. Additionally, the endpoints in a given range are to be included within the range. In thedisclosure and the claims, “and/or” means additionally or alternatively.Moreover, any use of a term in the singular also encompasses pluralforms.

As used herein, “comprising” is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. As usedherein, “consisting of” excludes any element, step, or ingredient notspecified in the claim element. As used herein, “consisting essentiallyof” does not exclude materials or steps that do not materially affectthe basic and novel characteristics of the claim. Any recitation hereinof the term “comprising”, particularly in a description of components ofa composition or in a description of elements of a device, is understoodto encompass those compositions and methods consisting essentially ofand consisting of the recited components or elements.

One of ordinary skill in the art will appreciate that startingmaterials, device elements, analytical methods, mixtures andcombinations of components other than those specifically exemplified canbe employed in the practice of the invention without resort to undueexperimentation. All art-known functional equivalents, of any suchmaterials and methods are intended to be included in this invention. Theterms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention that in theuse of such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. The invention illustratively described hereinsuitably may be practiced in the absence of any element or elements,limitation or limitations which is not specifically disclosed herein.Headings are used herein for convenience only.

All publications referred to herein are incorporated herein to theextent not inconsistent herewith. Some references provided herein areincorporated by reference to provide details of additional uses of theinvention. All patents and publications mentioned in the specificationare indicative of the levels of skill of those skilled in the art towhich the invention pertains. References cited herein are incorporatedby reference herein in their entirety to indicate the state of the artas of their filing date and it is intended that this information can beemployed herein, if needed, to exclude specific embodiments that are inthe prior art.

1. A substituted compound of general formula (I),

wherein X represents O or S; Y represents O, S or N—CN; Z representsN(R^(3b)) or C(R^(4a)R^(4b)); R¹ represents aryl or heteroaryl, whereinsaid aryl or heteroaryl may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from the groupconsisting of H, F, Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy;C₁₋₄-alkoxy-C₁₋₄-alkoxy; C₁₋₄-alkylS(═O), hydroxy-C₁₋₄-alkylS(═O),halo-C₁₋₄-alkylS(═O), cyano-C₁₋₄-alkylS(═O),C₁₋₄-alkoxy-C₁₋₄-alkylS(═O), C₁₋₄-alkylS(═O)₂, hydroxy-C₁₋₄-alkylS(═O)₂,halo-C₁₋₄-alkylS(═O)₂, cyano-C₁₋₄-alkylS(═O)₂,C₁₋₄-alkoxy-C₁₋₄-alkylS(═O)₂, H₂N, (C₁₋₄-alkyl)(H)N,(hydroxy-C₁₋₄-alkyl)(H)N, (halo-C₁₋₄-alkyl)(H)N, (cyano-C₁₋₄-alkyl)(H)N,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N, (C₃₋₆-cycloalkyl)(H)N,(C₃₋₇-heterocyclo-alkyl)(H)N, (C₁₋₄-alkyl)₂N,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N, (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N,(hydroxy-C₁₋₄-alkyl)₂N, (C₃₋₆-cyclo-alkyl)(hydroxy-C₁₋₄-alkyl)N,(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N, R² represents C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, C₃₋₆-cycloalkyl or (C₃₋₆-cycloalkyl)-C₁₋₄-alkyl;R^(3a) and R^(3b) each independently represent H, C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl orC₁₋₄-alkoxy-C₁₋₄-alkyl; R^(4a) and R^(4b) each independently representH, F, Cl, CN, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,cyano-C₁₋₄-alkyl or C₁₋₄-alkoxy-C₁₋₄-alkyl; or R^(4a) and R^(4b)together with the carbon atom connecting them form a C₃₋₆-cycloalkyl ora C₃₋₇-heterocycloalkyl; and Ar represents aryl or heteroaryl, whereinsaid aryl or heteroaryl may be condensed with an aromatic or aliphaticring to form a bicycle, and wherein said aryl or heteroaryl and saidcondensed aromatic or aliphatic ring each independently may beunsubstituted or mono- or independently polysubstituted by one or moresubstituents, selected from the group consisting of F, Cl, Br, CN, OH,═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy,cyano-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy,hydroxy-C₁₋₄-alkoxy-C₁₋₄-alkyl, C₁₋₄-alkylS(═O),hydroxy-C₁₋₄-alkylS(═O), halo-C₁₋₄-alkylS(═O), cyano-C₁₋₄-alkylS(═O),C₁₋₄-alkoxy-C₁₋₄-alkylS(═O), C₁₋₄-alkylS(═O)₂, hydroxy-C₁₋₄-alkylS(═O)₂,halo-C₁₋₄-alkylS(═O)₂, cyano-C₁₋₄-alkylS(═O)₂,C₁₋₄-alkoxy-C₁₋₄-alkylS(═O)₂, C₁₋₄-alkylS(═O)C₁₋₄-alkyl,hydroxy-C₁₋₄-alkylS(═O)C₁₋₄-alkyl, C₁₋₄-alkylS(═O)₂C₁₋₄-alkyl,hydroxy-C₁₋₄-alkylS(═O)₂C₁₋₄-alkyl, H₂N, (C₁₋₄-alkyl)(H)N,(hydroxy-C₁₋₄-alkyl)(H)N, (halo-C₁₋₄-alkyl)(H)N, (cyano-C₁₋₄-alkyl)(H)N,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N, (C₃₋₆-cycloalkyl)(H)N,(C₃₋₇-heterocycloalkyl)(H)N, (C₁₋₄-alkyl)₂N,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,(C₃₋₆-cyclo-alkyl)(C₁₋₄-alkyl)N, (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N,(hydroxy-C₁₋₄-alkyl)₂N, (C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)N,(C₃₋₇-heterocycloalkyl)-(hydroxy-C₁₋₄-alkyl)N, (H)₂NC₁₋₄-alkyl,[(C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl), [(hydroxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(halo-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(cyano-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(C₃₋₆-cycloalkyl)(H)N](C₁₋₄-alkyl),[(C₃₋₇-heterocycloalkyl)-(H)N](C₁₋₄-alkyl),[(C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),[(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(hydroxy-C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),[(C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₃₋₇-hetero-cycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl), H₂NC(═O),(C₁₋₄-alkyl)(H)NC(═O), (hydroxy-C₁₋₄-alkyl)(H)NC(═O),(halo-C₁₋₄-alkyl)(H)N—C(═O), (cyano-C₁₋₄-alkyl)(H)NC(═O),(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)—NC(═O), (C₃₋₆-cycloalkyl)(H)NC(═O),(C₃₋₇-heterocyclo-alkyl)(H)NC(═O), (C₁₋₄-alkyl)₂NC(═O),(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(C₃₋₆-cyclo-alkyl)(C₁₋₄-alkyl)NC(═O),(C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)NC(═O), (hydroxy-C₁₋₄-alkyl)₂NC(═O),(C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(═O),(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(═O), H₂NS(═O)₂,(C₁₋₄-alkyl)(H)NS(═O)₂, (hydroxy-C₁₋₄-alkyl)(H)NS(═O)₂,(halo-C₁₋₄-alkyl)(H)NS(═O)₂, (cyano-C₁₋₄-alkyl)(H)NS(═O)₂,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)NS(═O)₂, (C₃₋₆-cycloalkyl)(H)N S(═O)₂,(C₃₋₇-heterocycloalkyl)(H)NS(═O)₂, (C₁₋₄-alkyl)₂NS(═O)₂,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NS(═O)₂,(C₃₋₇-heterocyclo-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(hydroxy-C₁₋₄-alkyl)₂NS(═O)₂,(C₃₋₆-cyclo-alkyl)(hydroxy-C₁₋₄-alkyl)NS(═O)₂,(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NS(═O)₂,H₂NS(═O)₂N(H)C₁₋₄-alkyl, (C₁₋₄-alkyl)(H)NS(═O)₂N(H)C₁₋₄-alkyl,(hydroxy-C₁₋₄-alkyl)(H)NS(═O)₂N(H)C₁₋₄-alkyl,(C₁₋₄-alkyl)₂NS(═O)₂N(H)C₁₋₄-alkyl, (C₁₋₄-alkyl)S(═O)₂N(H)C₁₋₄-alkyl,(hydroxy-C₁₋₄-alkyl)S(═O)₂N(H)C₁₋₄-alkyl, C₃₋₆-cycloalkyl,(C₃₋₆-cycloalkyl)-C₁₋₄-alkyl, (C₃₋₆-cycloalkyl)-C₁₋₄-alkoxy,C₃₋₇-hetero-cycloalkyl, (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkyl,(C₃₋₇-heterocycloalkyl)-C₁₋₄-alkoxy, wherein said C₃₋₆-cycloalkyl orC₃₋₇-heterocycloalkyl may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from H, F, Cl, Br,CN, OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy; aryl,heteroaryl, (aryl)C₁₋₄-alkyl or (heteroaryl)C₁₋₄-alkyl, wherein saidaryl or heteroaryl may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from the groupconsisting of H, F, Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy andC₁₋₄-alkoxy-C₁₋₄-alkoxy; optionally in the form of a single stereoisomeror a mixture of stereoisomers, in the form of the free compound and/or aphysiologically acceptable salt or a solvate thereof.
 2. The substitutedcompound according to claim 1, wherein Y represents O.
 3. Thesubstituted compound according to claim 1, wherein R^(3a) represents H.4. The substituted compound according to claim 1, wherein Z representsN(R^(3b)), wherein R^(3b) represents H; or Z represents C(R^(4a)R^(4b)),wherein R^(4a) represents CH₃ and R^(4b) represents H or wherein R^(4a)and R^(4b) each represent H.
 5. The substituted compound according toclaim 1, wherein R² represents CH₃, CFH₂, CHF₂, CF₃, CH₂CH₃, CH(CH₃)₂ orC(CH₃)₃.
 6. The substituted compound according to claim 1, wherein R¹represents

wherein n is 0, 1, 2 or 3; R⁵ represents F, Cl, Br, CN, C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, andC₁₋₄-alkoxy-C₁₋₄-alkoxy and each R⁶ independently is selected from thegroup consisting of F, Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₄-alkoxy, C₁₋₄-alkylS(═O), hydroxy-C₁₋₄-alkylS(═O),C₁₋₄-alkylS(═O)₂, hydroxy-C₁₋₄-alkylS(═O)₂, H₂N, (C₁₋₄-alkyl)(H)N,(hydroxy-C₁₋₄-alkyl)(H)N, (C₁₋₄-alkyl)₂N,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (hydroxy-C₁₋₄-alkyl)₂N,[(C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl), [(hydroxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),[(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl), H₂NC(═O),(C₁₋₄-alkyl)(H)NC(═O), (hydroxy-C₁₋₄-alkyl)(H)NC(═O),(C₁₋₄-alkyl)₂NC(═O), (hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(hydroxy-C₁₋₄-alkyl)₂NC(═O), H₂NS(═O)₂ (C₁₋₄-alkyl)(H)NS(═O)₂,(hydroxy-C₁₋₄-alkyl)(H)NS(═O)₂, (C₁₋₄-alkyl)₂NS(═O)₂,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂, (hydroxy-C₁₋₄-alkyl)₂NS(═O)₂,C₃₋₆-cycloalkyl, (C₃₋₆-cycloalkyl)-C₁₋₄-alkyl,(C₃₋₆-cycloalkyl)-C₁₋₄-alkoxy, C₃₋₇-heterocycloalkyl,(C₃₋₇-heterocycloalkyl)-C₁₋₄-alkyl, (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkoxy,wherein said C₃₋₆-cycloalkyl or C₃₋₇-heterocycloalkyl may beunsubstituted or mono- or independently polysubstituted by one or moresubstituents, selected from H, F, Cl, Br, CN, OH, ═O, C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy,cyano-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy; aryl, heteroaryl,(aryl)C₁₋₄-alkyl or (heteroaryl)C₁₋₄-alkyl, wherein said aryl orheteroaryl may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from the groupconsisting of H, F, Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy andC₁₋₄-alkoxy-C₁₋₄-alkoxy.
 7. The substituted compound according to claim1, wherein the compound of general formula (I) has general formula (Ia)

wherein X represents O or S; Z represents N(R^(3b)) or C(R^(4a)R^(4b));n is 0, 1 or 2; R² represents CH₃, CFH₂, CHF₂, CF₃, CH₂CH₃, CH(CH₃)₂ orC(CH₃)₃, R^(3b) independently represent H, C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl orC₁₋₄-alkoxy-C₁₋₄-alkyl; R^(4a) and R^(4b) each independently representH, F, Cl or C₁₋₄-alkyl; R⁵ represents F, Cl, Br, CN, C₁₋₄-alkyl,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, andC₁₋₄-alkoxy-C₁₋₄-alkoxy and each R⁶ independently is selected from thegroup consisting of F, Cl, Br, CN, OH, C₁₋₄-alkyl, CF₃,hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy,cyano-C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkoxy, C₁₋₄-alkylS(═O),C₁₋₄-alkylS(═O)₂, H₂N, (C₁₋₄-alkyl)(H)N, (C₁₋₄-alkyl)₂N, H₂NC(═O),(C₁₋₄-alkyl)(H)NC(═O) and (C₁₋₄-alkyl)₂NC(═O); and Ar represents aryl orheteroaryl, wherein said aryl or heteroaryl may be condensed with anaromatic or aliphatic ring to form a bicycle, and wherein said aryl orheteroaryl and said condensed aromatic or aliphatic ring eachindependently may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from the groupconsisting of F, Cl, Br, CN, OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₄-alkoxy, hydroxy-C₁₋₄-alkoxy-C₁₋₄-alkyl,C₁₋₄-alkylS(═O), hydroxy-C₁₋₄-alkylS(═O), halo-C₁₋₄-alkylS(═O),cyano-C₁₋₄-alkylS(═O), C₁₋₄-alkoxy-C₁₋₄-alkylS(═O), C₁₋₄-alkylS(═O)₂,hydroxy-C₁₋₄-alkylS(═O)₂, halo-C₁₋₄-alkylS(═O)₂, cyano-C₁₋₄-alkylS(═O)₂,C₁₋₄-alkoxy-C₁₋₄-alkylS(═O)₂, C₁₋₄-alkylS(═O)C₁₋₄-alkyl,hydroxy-C₁₋₄-alkylS(═O)C₁₋₄-alkyl, C₁₋₄-alkylS(═O)₂C₁₋₄-alkyl,hydroxy-C₁₋₄-alkylS(═O)₂C₁₋₄-alkyl, H₂N, (C₁₋₄-alkyl)(H)N,(hydroxy-C₁₋₄-alkyl)(H)N, (halo-C₁₋₄-alkyl)(H)N, (cyano-C₁₋₄-alkyl)(H)N,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N, (C₃₋₆-cycloalkyl)(H)N,(C₃₋₇-heterocycloalkyl)(H)N, (C₁₋₄-alkyl)₂N,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N, (C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N,(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N, (C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N,(hydroxy-C₁₋₄-alkyl)₂N, (C₃₋₆-cyclo-alkyl)(hydroxy-C₁₋₄-alkyl)N,(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N, (H)₂NC₁₋₄-alkyl,[(C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl), [(hydroxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(halo-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(cyano-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)N](C₁₋₄-alkyl),[(C₃₋₆-cycloalkyl)(H)N](C₁₋₄-alkyl),[(C₃₋₇-heterocycloalkyl)(H)N](C₁₋₄-alkyl), [(C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),[(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₃₋₇-heterocycloalkyl)(C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(hydroxy-C₁₋₄-alkyl)₂N](C₁₋₄-alkyl),[(C₃₋₆-cyclo-alkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl),[(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)N](C₁₋₄-alkyl), H₂NC(═O),(C₁₋₄-alkyl)(H)NC(═O), (hydroxy-C₁₋₄-alkyl)(H)NC(═O),(halo-C₁₋₄-alkyl)(H)NC(═O), (cyano-C₁₋₄-alkyl)(H)NC(═O),(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)NC(═O), (C₃₋₆-cycloalkyl)-(H)NC(═O),(C₃₋₇-heterocycloalkyl)(H)NC(═O), (C₁₋₄-alkyl)₂NC(═O),(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)N—C(═O),(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O),(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NC(═O),(C₃₋₇-heterocyclo-alkyl)(C₁₋₄-alkyl)NC(═O), (hydroxy-C₁₋₄-alkyl)₂NC(═O),(C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(═O),(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NC(═O), H₂NS(═O)₂,(C₁₋₄-alkyl)(H)NS(═O)₂, (hydroxy-C₁₋₄-alkyl)(H)NS(═O)₂,(halo-C₁₋₄-alkyl)(H)NS(═O)₂, (cyano-C₁₋₄-alkyl)(H)N—S(═O)₂,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(H)NS(═O)₂, (C₃₋₆-cycloalkyl)(H)NS(═O)₂,(C₃₋₇-heterocycloalkyl)(H)NS(═O)₂, (C₁₋₄-alkyl)₂NS(═O)₂,(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(halo-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(cyano-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(C₁₋₄-alkoxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(C₃₋₆-cycloalkyl)(C₁₋₄-alkyl)NS(═O)₂,(C₃₋₇-heterocyclo-alkyl)(C₁₋₄-alkyl)NS(═O)₂,(hydroxy-C₁₋₄-alkyl)₂NS(═O)₂,(C₃₋₆-cycloalkyl)(hydroxy-C₁₋₄-alkyl)NS(═O)₂,(C₃₋₇-heterocycloalkyl)(hydroxy-C₁₋₄-alkyl)NS(═O)₂,H₂NS(═O)₂N(H)C₁₋₄-alkyl, (C₁₋₄-alkyl)(H)N—S(═O)₂N(H)C₁₋₄-alkyl,(hydroxy-C₁₋₄-alkyl)(H)NS(═O)₂N(H)C₁₋₄-alkyl,(C₁₋₄-alkyl)₂NS(═O)₂N(H)C₁₋₄-alkyl, (C₁₋₄-alkyl)S(═O)₂N(H)C₁₋₄-alkyl,(hydroxy-C₁₋₄-alkyl)S(═O)₂N(H)C₁₋₄-alkyl, C₃₋₆-cycloalkyl,(C₃₋₆-cyclo-alkyl)-C₁₋₄-alkyl, (C₃₋₆-cycloalkyl)-C₁₋₄-alkoxy,C₃₋₇-heterocycloalkyl, (C₃₋₇-heterocycloalkyl)-C₁₋₄-alkyl,(C₃₋₇-heterocycloalkyl)-C₁₋₄-alkoxy, wherein said C₃₋₆-cycloalkyl orC₃₋₇-heterocycloalkyl may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from H, F, Cl, Br,CN, OH, ═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy,halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy and C₁₋₄-alkoxy-C₁₋₄-alkoxy; aryl,heteroaryl, (aryl)C₁₋₄-alkyl or (heteroaryl)C₁₋₄-alkyl, wherein saidaryl or heteroaryl may be unsubstituted or mono- or independentlypolysubstituted by one or more substituents, selected from the groupconsisting of H, F, Cl, Br, CN, OH, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl,hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, cyano-C₁₋₄-alkoxy andC₁₋₄-alkoxy-C₁₋₄-alkoxy; optionally in the form of a single stereoisomeror a mixture of stereoisomers, in the form of the free compound and/or aphysiologically acceptable salt or a solvate thereof.
 8. The substitutedcompound according to claim 7, wherein n is
 0. 9. The substitutedcompound according to claim 1, wherein R⁵ is F, Cl, CN, CH₃, CHF₂, CF₃,CH₂CH₃, OCH₃, OCF₃, OCHF₂ or CH₂OCH₃.
 10. The substituted compoundaccording to claim 1, wherein Ar is selected from phenyl or pyridinyl,wherein said phenyl or pyridinyl may be condensed with an aromatic oraliphatic ring to form a bicycle, and wherein said phenyl or pyridinyland said condensed aromatic or aliphatic ring each independently may beunsubstituted or mono- or independently polysubstituted by one or moresubstituents, selected from the group consisting of F, Cl, Br, CN, OH,═O, C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyl, halo-C₁₋₄-alkyl,C₁₋₄-alkoxy-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₄-alkoxy, H₂N, (C₁₋₄-alkyl)(H)N,(hydroxy-C₁₋₄-alkyl)(H)N, H₂NC(═O), (C₁₋₄-alkyl)(H)NC(═O),(hydroxy-C₁₋₄-alkyl)(H)NC(═O), (C₁₋₄-alkyl)₂NC(═O),(hydroxy-C₁₋₄-alkyl)(C₁₋₄-alkyl)NC(═O) and C₃₋₆-cycloalkyl.
 11. Thesubstituted compound according to claim 1, wherein Ar is selected from

each unsubstituted or mono- or independently polysubstituted by one ormore substituents, wherein said substituent(s) are selected from thegroup consisting of F, Cl, Br, CN, ═O, OH, CH₃, CHF₂, CF₃, CH₂CH₃,(CH₂)₂CH₃, CH(CH₃)₂, (CH₂)₃CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃,OCH₃, OCF₃, OCHF₂, CH₂OCH₃, CH₂OCF₃, CH₂OH, CH₂CH₂OH, OCH₂CH₂OH,N(H)CH₂CH₂OH, N(CH₃)CH₂CH₂OH, CH₂OCH₂CH₂OH, CH₂N(H)CH₂CH₂OH,CH₂N(CH₃)CH₂CH₂OH, CH₂CH₂S(═O)₂CH₃, CH₂CH₂S(═O)₂N(H)CH₃,CH₂N(H)S(═O)₂NH₂, CH₂N(H)S(═O)₂CH₃,


12. The substituted compound according to claim 1, wherein Ar isselected from

wherein G is CH or CF.
 13. A pharmaceutical composition comprising atleast one substituted compound according to claim
 1. 14. A substitutedcompound according to claim 1 for use in the treatment and/orprophylaxis of one or more diseases and/or disorders selected from thegroup consisting of pain.
 15. A method of treatment and/or prophylaxisof disorders and/or diseases selected from the group consisting of painin a mammal comprising administering an effective amount of at least onecompound according to claim 1 to the mammal.
 16. The substitutedcompound according to claim 4, wherein Z represents N(R^(3b)), whereinR^(3b) represents H.
 17. The substituted compound according to claim 5,wherein R² represents CF₃ or C(CH₃)₃.
 18. The substituted compoundaccording to claim 14, wherein the pain is selected from the groupconsisting of acute pain, chronic pain, neuropathic pain, visceral painand joint pain.
 19. The method according to claim 15, wherein the painis selected from the group consisting of acute pain, chronic pain,neuropathic pain, visceral pain and joint pain.